New vitamin D derivatives with cyclic substructures in the side chains, process and intermediate products for their production, and the use for the production of pharmaceutical agents

ABSTRACT

The invention relates to vitamin D derivatives of general formula I,  
                 
 
     process for their production, intermediate products of the process as well as the use for the production of pharmaceutical agents.

[0001] The invention relates to new vitamin D derivatives of generalformula I

[0002] process for their production, intermediate products of theprocess as well as the use for the production of pharmaceutical agents.

[0003] Prior Art

[0004] Natural vitamins D₂ and D₃ are inherently biologically inactiveand are converted into biologically active metabolites [1α,25-dihydroxyvitamin D₃ (calcitriol) or -D₂] only after hydroxylation at C-atom 25 inthe liver and at C-atom 1 in the kidney. The action of the activemetabolites involves the regulation of the calcium and phosphateconcentration in the serum; they counteract a dropping of the calciumconcentration in the serum by increasing the calcium absorption in theintestine and under certain circumstances promoting calcium mobilizationfrom the bones. FIG. 1 shows the structure of some known vitamin Dderivatives:

[0005] In addition to their pronounced effect on the calcium-andphosphate metabolism, the active metabolites of vitamin D₂ and vitaminD₃ and their synthetic derivatives have a proliferation-inhibiting anddifferentiation-stimulating action on tumor cells and normal cells, suchas, for example, skin cells. In addition, a pronounced effect on cellsof the immune system (inhibiting of proliferation-andinterleukin-2-synthesis of lymphocytes, increase of cytotoxicity andphagocytosis in vitro of monocytes) has been found, which manifestsitself in an immunomodulatory action. Finally, because of a stimulatingaction on bone-forming cells, an increased formation of bone in normaland osteoporotic rats is found [R. Bouillon et al. “Short Term Course of1,25(OH)₂D₃ Stimulates Osteoblasts But Not Osteoclasts,” Calc. TissueInt. 49, 168 (1991)]. All actions are mediated by binding to the vitaminD receptor. Because of the binding, the activity of specific genes isregulated.

[0006] When using biologically active metabolites of vitamins D₂ and D₃,a toxic effect on the calcium metabolism is produced (hypercalcemia).

[0007] By structural manipulations of the side chain, therapeuticallyusable effectiveness can be separated from undesirable hypercalcemicactivity. A suitable structural variant is the introduction of a24-hydroxy group.

[0008] 1α-Cholecalciferols that are hydroxylated in 24-position arealready described in DE 25 26 981. They have a lower toxicity than thecorresponding non-hydroxylated 1α-cholecalciferol. Further, 24-hydroxyderivatives are described in the following patent applications: DE 39 33034, DE 40 03 854, DE 40 34 730 (?), EP 0 421 561, EP 0 441 467, WO87/00834, and WO 91/12238.

[0009] Finally, 25-carboxylic acid derivatives of calcitriol that arehydroxylated at C-24 are described in WO 94/07853, and said derivativesexhibit a more advantageous spectrum of action than calcitriol. Theequivalent is also true for new vitamin D derivatives with othersubstituents at C-25 (WO 97/00242). While the ability to trigger ahypercalcemia is considerably weakened, proliferation-inhibiting anddifferentiation-stimulating actions are maintained. Generally, however,the introduction of the 24-hydroxyl group results in metabolicdestabilization of the derivatives. For this reason, these compounds areonly conditionally suitable for systemic administration.

[0010] There is therefore a need for new vitamin D derivatives that haveas advantageous or improved a spectrum of action as the compounds thatare described in the prior art (especially Wo 94/07853 and WO 97/00242),but that are better suited for systemic administration owing to theirhigher metabolic stability.

[0011] The object of this patent application is therefore to makeavailable such vitamin D derivatives. This object is achieved by thecompounds that are disclosed in the claims.

[0012] This invention therefore relates to vitamin D derivatives ofgeneral formula I,

[0013] in which

[0014] Y₁ and Y₂, independently of one another, each mean a hydrogenatom or a group —C(O)R₅,

[0015] and Y₃ means a hydrogen atom or a hydroxy group, a halogen atom,a group —OC(O)R₅ or an —OR₅ group,

[0016] whereby

[0017] R₅ stands for an aromatic radical with 5 to 12 C atoms or for analiphatic, straight-chain or branched, saturated or unsaturated C₁-C₁₂alkyl radical, which optionally is interrupted by 1-2 oxygen atoms, 1-2sulfur atoms and/or 1-2 NH groups and/or optionally is substituted by1-2 hydroxy groups, 1-2 amino groups, 1-2 SH groups, 1-2 COOH groupsand/or 1-2 phenyl groups,

[0018] and the group Y₃ can be present both in the 2α-situation and theepimeric 2β-situation,

[0019] R₁ and R₂ each mean a hydrogen atom or together an exocyclicmethylene group,

[0020] R₃ and R₄, independently of one another, mean a hydrogen atom, afluorine, chlorine or bromine atom, an alkyl group with 1 to 4 carbonatoms, together a methylene group or together with quaternary carbonatom 20 a 3-to 7-membered, saturated or unsaturated carbocyclic ring,

[0021] Q means a straight-chain alkylene group with 1 to 5 carbon atoms,

[0022] X₁ and X₂ together mean a double-bound keto-oxygen atom or,independently of one another, a hydrogen atom, a hydroxy group, an—OC(O)R₅ group, a fluorine, chlorine or bromine atom,

[0023] whereby X₁ and X₂, not at the same time, each should be a hydroxygroup or each an —OC(O)R₅ group,

[0024] Z means a carbocyclic or heterocyclic, optionally aromatic orheteroaromatic ring with 5 or 6 ring members or a condensed ring systemthat consists of a 5- and a 6-membered ring or two 6-membered rings,which can be substituted by one or more fluorine, chlorine, bromine oriodine atoms, one or more hydroxy groups, one or more COOR₆ groups, oneor more C₁-C₅ alkyl groups, which in turn can be substituted by one ormore fluorine, chlorine, bromine or iodine atoms, C₁-C₆ alkoxy groupsand/or COOR₆ groups,

[0025] whereby

[0026] R₆ stands for a C₁-C₆ alkyl group, a benzyl group or a phenylgroup,

[0027] and all possible epimers or diastereomers and mixtures thereof.

[0028] The invention also relates to a process for the production of thecompounds according to the invention, intermediate products in theproduction process as well as the use of the compounds according to theinvention for the production of pharmaceutical agents.

[0029] Especially advantageous embodiments of the invention are thesubject of the subclaims.

[0030] The group —C(O)R₅, which is defined for Y₁ and Y₂, can carry 1 to13 carbon atoms and is derived especially from saturated carboxylicacids. The radicals can be cyclic, acyclic, straight-chain or branched,saturated or unsaturated, carbocyclic or heterocyclic. The radicals arepreferably derived from C₁-C₉ carboxylic acids. For example, formicacid, acetic acid, propionic acid, butanoic acid, pentanoic acid andpivalic acid can be mentioned. The groups Y₁ and Y₂, independently ofone another, especially preferably can each mean a hydrogen atom or anacetyl, propionyl or pivaloyl group.

[0031] This explanation is also used for the group —OC(O)R₅, which isdefined for the radicals Y₃, X₁ and X₂.

[0032] The group Y₃ can mean a hydrogen atom, a fluorine, chlorine orbromine atom or a hydroxy group, an OR₅ group or an —OC(O)R₅ group.

[0033] The alkoxy group Y₃ can mean straight-chain or branched,preferably unsubstituted and without interruption of heteroatoms, e.g.,methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy. Thepreferred chain length is C₁-C₉.

[0034] Groups R₃ and R₄, independently of one another, can each mean afluorine, chlorine or bromine atom, an alkyl group with 1 to 4 carbonatoms (methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl),together a methylene group or together with quaternary carbon atom 20 a3- to 7-membered, saturated or unsaturated carbocyclic ring.

[0035] For R₃ and R₄, the following preferred combinations apply: R₃=H,R₄=methyl or R₃=methyl, R₄H; R₃=R₄=methyl; R₃ and R₄ together form amethylene group or together with tertiary carbon atom 20 form acyclopropyl ring.

[0036] Optional radical R₅ from the radical —OC(O)R₅ that is defined forY₃, X₁ and X₂ is an organic radical with 1 to 12 C atoms, which arederived from longer carboxylic acids corresponding to a carbon atom.These radicals can be saturated or unsaturated, branched or unbranched,saturated or unsaturated, acyclic, carbocyclic or heterocyclic. Examplesof radicals R₅ are methyl, ethyl, propyl, i-propyl, butyl or phenylgroups. The radicals of naturally occurring amino acids are alsopossible, however.

[0037] Preferred radical R₅ is derived from C₁ to C₉, especially C₂ toC₅ alkanecarboxylic acids, such as, for example, acetic acid, propionicacid, butyric acid or pivaloyl acid. Among the aromatic groups, thephenyl group and substituted phenyl groups are preferred.

[0038] Alkyl group R₆ can be straight-chain or branched, saturated orunsaturated, and it can mean, e.g., methyl, ethyl, propyl, butyl,isobutyl, tert-butyl, pentyl, isopentyl, neopentyl or hexyl.

[0039] The benzyl group and the phenyl group R₆ can be unsubstituted orelse substituted by one or more halogen atom(s), hydroxy group(s), C₁-C₄alkoxy group(s), CF₃ group(s) or amino group(s). The unsubstitutedbenzyl and phenyl groups are preferred.

[0040] Q is preferably to mean a methylene, ethylene or propylene group.

[0041] X₁ and X₂ preferably together are to mean a carbonyl group

[0042] or X₁ means a hydroxyl group or a fluorine atom and X₂ means ahydrogen atom

[0043] or X₁ means a hydrogen atom and X₂ means a hydroxyl group or afluorine atom

[0044] or X₁ means an —OC(O)R₆ group and X₂ means a hydrogen atom

[0045] or X₁ means a hydrogen atom and X₂ means an —OC(O)R₆ group.

[0046] The two cases in which X₁═X₂═OH or X₁═X₂═O—C(O)R₆ were ruled out,since they are not chemically useful.

[0047] Z is preferably to mean a phenyl ring, which is substituted inortho-, meta- or para-position with one or more methoxy, ethoxy,propoxy, hydroxy, fluorine, chlorine, bromine, methyl, ethyl, propyl ortrifluoromethyl groups or Z is preferably to mean a heterocyclic system,such as, e.g., a furan, thiophene, pyrazole, pyrrole, oxazole, thiazole,imidazole ring, which can carry one or more methyl, ethyl or propylgroups at any position(s), which in turn can be substituted by halogenof the hydroxy groups and can be linked with the initial system via anyC-atom, or Z is preferably to mean a heterocyclic condensed system, suchas, e.g., a benzofuran, benzothiophene, benzimidazole, benzoxazole,benzothiazole, indole system, which can carry methyl, ethyl or propylgroups at any position, which in turn can be substituted by halogen ofthe hydroxy groups and can be linked with the initial system via anyC-atom.

[0048] If the term halogen is used, fluorine, chlorine, bromine oriodine in connection with substitution patterns of radicals andpreferably bromine or iodine as leaving groups in the process are meant.

[0049] Of the compounds of general formula I according to the invention,the following compounds are quite especially preferred:

[0050](7E)-(1R,3R,24aR)-24a-(Oxazol-4-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0051](7E)-(1R,3R,24aS)-24a-(oxazol-4-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0052](5Z,7E)-(1S,3R,24aR)-24a-(oxazol-4-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol

[0053](5Z,7E)-(1S,3R,24aS)-24a-(oxazol-4-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol

[0054](7E)-(1R,3R,24aR)-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0055](7E)-(1R,3R,24aS)-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0056](7E)-(1R,3R)-1,3-dihydroxy-24a-(thiazol-2-yl-)-24-a-homo-19-nor-9,10-secochola-5,7-dien-24a-one

[0057](5Z,7E)-(1S,3R,24aR)-24a-(thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol

[0058](5Z,7E)-(1S,3R,24aS)-24a-(thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol

[0059](5Z,7E)-(1S,3R)-1,3-dihydroxy-24a-(thiazol-2-yl-)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one

[0060](7E)-(1R,3R,24aR)-24a-(4-methylthiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0061](7E)-(1R,3R,24aS)-24a-(4-methylthiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0062](7E)-(1R,3R)-1,3-dihydroxy-24a-(4-methylthiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one

[0063](5Z,7E)-(1S,3R,24aR)-24a-(4-methylthiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol

[0064](5Z,7E)-(1S,3R,24aS)-24a-(4-methylthiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol

[0065](5Z,7E)-(1S,3R)-1,3-dihydroxy-24a-(4-methylthiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one

[0066](7E)-(1R,3R,24aR)-24a-(thien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0067](7E)-(1R,3R,24aS)-24a-(thien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0068](7E)-(1R,3R)-1,3-dihydroxy-24a-(thien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one

[0069](5Z,7E)-(1S,3R,24aR)-24a-(thien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol

[0070](5Z,7E)-(1S,3R,24aS)-24a-(thien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol

[0071](7E)-(1R,2S,3R,24aR)-24a-thien-2-yl-24a-homo-19-nor-9,10-secochola-5,7-diene-1,2,3,24-tetrol

[0072](7E)-(1R,2S,3R,24aS)-24a-thien-2-yl-24a-homo-19-nor-9,10-secochola-5,7-diene-1,2,3,24-tetrol

[0073](7E)-(1R,2S,3R)-24a-thien-2-yl-1,2,3-trihydroxy-24a-homo-9,10-secochola-5,7-dien-24a-one

[0074](7E)-(1R,3R,24aR)-24a-(4-methylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0075](7E)-(1R,3R,24aS)-24a-(4-methylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0076](7E)-(1R,3R)-1,3-dihydroxy-24a-(4-methylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one

[0077](5Z,7E)-(1S,3R,24aR)-24a-(4-methylthien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol

[0078](5Z,7E)-(1S,3R,24aS)-24a-(4-methylthien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol

[0079](5Z,7E)-(1S,3R)-1,3-dihydroxy-24a-(4-methylthien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one

[0080](7E)-(1R,2S,3R,24aR)-24a-(4-methylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,2,3,24-tetrol

[0081](7E)-(1R,2S,3R,24aS)-24a-(4-methylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,2,3,24-tetrol

[0082](7E)-(1R,2S,3R)-24a-(4-methylthien-2-yl)-1,2,3-trihydroxy-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one

[0083](7E)-(1R,3R,24aR)-24a-(5-ethylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0084](7E)-(1R,3R,24aS)-24a-(5-ethylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0085](7E)-(1R,3R,24aR)-24a-[5-(2-hydroxyethyl)-4-methylthiazol-2-yl]-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0086](7E)-(1R,3R,24aS)-24a-[5-(2-hydroxyethyl)-4-methylthiazol-2-yl]-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0087](7E)-(1R,3R)-1,3-dihydroxy-24a-[5-(2-hydroxyethyl)-4-methylthiazol-2-yl]-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one

[0088](7E)-(1R,3R,24aR)-24a-(benzothiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0089](7E)-(1R,3R,24aS)-24a-(benzothiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0090](7E)-(1R,3R)-24a-(benzothiazol-2-yl)-1,3-dihydroxy-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one

[0091](7E)-(1R,3R,24aR)-24a-(benzofuran-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0092](7E)-(1R,3R,24aS)-24a-(benzofuran-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0093](7E)-(1R,3R)-24a-(benzofuran-2-yl)-1,3-dihydroxy-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one

[0094](7E)-(1R,3R,24aR)-24a-(benzothiophen-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0095](7E)-(1R,3R,24aS)-24a-(benzothiophen-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0096](7E)-(1R,3R)-24a-(benzothiophen-2-yl)-1,3-dihydroxy-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one

[0097](7E)-(1R,3R,24aR)-24a-(1-methylbenzimidazol-2-yl)-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0098](7E)-(1R,3R,24aS)-24a-(1-methylbenzimidazol-2-yl)-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0099](7E)-(1R,3R)-1,3-dihydroxy-24a-(1-methylbenzimidazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one

[0100](7E)-(1R,3R)-1-(1,3-dihydroxy-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-yl)-3-[(4-methoxyphenyl)-methoxy]-1H-pyrazole-4-carboxylicacid ethyl ester

[0101](7E)-(1R,3R)-1-(1,3-dihydroxy-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-yl)-3-hydroxy-1H-pyrazole-4-carboxylicacid ethyl ester

[0102](7E)-(1R,3R,24aR)-24a-(4-methylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0103](7E)-(1R,3R,24aS)-24a-(4-methylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0104](7E)-(1R,3R)-1,3-dihydroxy-24a-(4-methylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one

[0105](7E)-(1R,2R,3R,24aR)-24a-(4-methylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,2,3,24a-tetrol

[0106](7E)-(1R,RS,3R,24aS)-24a-(4-methylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,2,3,24a-tetrol

[0107](7E)-(1R,3R,24aR)-24a-(4-trifluoromethylphenyl)-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0108](7E)-(1R,3R,24aS)-24a-(4-trifluoromethylphenyl)-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0109](7E)-(1R,3R)-1,3-dihydroxy-24a-(4-trifluoromethylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one

[0110](7E)-(1R,3R,24aR)-24a-(4-methoxyphenyl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0111](7E)-(1R,3R,24aS)-24a-(4-methoxyphenyl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0112](7E)-(1R,3R)-1,3-dihydroxy-24a-(4-methoxyphenyl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one

[0113](7E)-(1R,3R,20S,24aR)-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0114](7E)-(1R,3R,20S,24aS)-24a-(thiazol-2-yl)-24-a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0115](7E)-(1R,3R,20S)-1,3-dihydroxy-24a-(thiazol-2-yl)-24-a-homo-19-nor-9,10-secochola-5,7-dien-24a-one

[0116](5Z,7E)-(1S,3R,20S,24aR)-24a-(thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol

[0117](5Z,7E)-(1S,3R,20S,24aS)-24a-(thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol

[0118](5Z,7E)-(1S,3R,20S)-1,3-dihydroxy-24a-(thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one

[0119](5Z,7E)-(1S,3R,24S)-24-(thiazol-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol

[0120](5Z,7E)-(1S,3R,24R)-24-(thiazol-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol

[0121](5Z,7E)-(1S,3R)-1,3-dihydroxy-24-(thiazol-2-yl)-9,10-secochola-5,7,10(19)-trien-24-one

[0122](7E)-(1R,3R,20S,24aR)-24a-(oxazol-4-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0123](7E)-(1R,3R,20S,24aS)-24a-(oxazol-4-yl)-24-a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0124](7E)-(1R,3R,20S)-1,3-dihydroxy-24a-(oxazol-4-yl)-24-a-homo-19-nor-9,10-secochola-5,7-dien-24a-one

[0125](5Z,7E)-(1S,3R,20S,24aR)-24a-(oxazol-4-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol

[0126](5Z,7E)-(1S,3R,20S,24aS)-24a-(oxazol-4-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol

[0127](5Z,7E)-(1S,3R,20S)-1,3-dihydroxy-24a-(oxazol-4-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one

[0128](5Z,7E)-(1S,3R,24R)-24-(oxazol-4-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol

[0129](5Z,7E)-(1S,3R,24S)-24-(oxazol-4-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol

[0130](5Z,7E)-(1S,3R)-1,3-dihydroxy-24-(oxazol-4-yl)-9,10-secochola-5,7,10(19)-trien-24-one

[0131](7E)-(1R,3R,20S,24aR)-24a-(4-methylthiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0132](7E)-(1R,3R,20S,24aS)-24a-(4-methylthiazol-2-yl)-24-a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0133](7E)-(1R,3R,20S)-1,3-dihydroxy-24a-(4-methylthiazol-2-yl)-24-a-homo-19-nor-9,10-secochola-5,7-dien-24a-one

[0134](5Z,7E)-(1S,3R,20S,24aR)-24a-(4-methylthiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol

[0135](5Z,7E)-(1S,3R,20S,24aS)-24a-(4-methylthiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol

[0136](5Z,7E)-(1S,3R,20S)-1,3-dihydroxy-24a-(4-methylthiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one

[0137](5Z,7E)-(1S,3R,24R)-24-(4-methylthiazol-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol

[0138](5Z,7E)-(1S,3R,24S)-24-(4-methylthiazol-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol

[0139](5Z,7E)-(1S,3R)-1,3-dihydroxy-24-(4-methylthiazol-2-yl)-9,10-secochola-5,7,10(19)-trien-24-one

[0140](7E)-(1R,3R,20S,24aR)-24a-(4-methylthien-2-yl)-24a-homo-19-(7E)-(1R,3R,20S,24aS)-24a-(4-methylthien-2-yl)-24-a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0141](7E)-(1R,3R,20S)-1,3-dihydroxy-24a-(4-methylthien-2-yl)-24-a-homo-19-nor-9,10-secochola-5,7-dien-24a-one

[0142](5Z,7E)-(1S,3R,20S,24aR)-24a-(4-methylthien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol

[0143](5Z,7E)-(1S,3R,20S,24aS)-24a-(4-methylthien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol

[0144](5Z,7E)-(1S,3R,20S)-1,3-dihydroxy-24a-(4-methylthien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one

[0145](5Z,7E)-(1S,3R,24R)-24-(4-methylthien-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol

[0146](5Z,7E)-(1S,3R,24S)-24-(4-methylthien-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol

[0147](5Z,7E)-(1S,3R)-1,3-dihydroxy-24-(4-methylthien-2-yl)-9,10-secochola-5,7,10(19)-trien-24-one

[0148](7E)-(1R,3R,20S,24aR)-24a-(thien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0149](7E)-(1R,3R,20S,24aS)-24a-(thien-2-yl)-24-a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0150](7E)-(1R,3R,20S)-1,3-dihydroxy-24a-(thien-2-yl)-24-a-homo-19-nor-9,10-secochola-5,7-dien-24a-one

[0151](5Z,7E)-(1S,3R,20S,24aR)-24a-(thien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol

[0152](5Z,7E)-(1S,3R,20S,24aS)-24a-(thien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol

[0153](5Z,7E)-(1S,3R,20S)-1,3-dihydroxy-24a-(thien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one

[0154](5Z,7E)-(1S,3R,24R)-24-(thien-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol

[0155](5Z,7E)-(1S,3R,24S)-24-(thien-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol

[0156](5Z,7E)-(1S,3R)-1,3-dihydroxy-24-(thien-2-yl)-9,10-secochola-5,7,10(19)-trien-24-one

[0157](5Z,7E)-(1S,3R,24S)-24-(4-methylthiazol-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol

[0158](5Z,7E)-(1S,3R,24R)-24-(4-methylthiazol-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol

[0159](5Z,7E)-(1S,3R)-1,3-dihydroxy-24-(4-methylthiazol-2-yl)-9,10-secochola-5,7,10(19)-trien-24-one

[0160](5Z,7E)-(1S,3R,24S)-24-(thien-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol

[0161](5Z,7E)-(1S,3R,24R)-24-(thien-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol

[0162](5Z,7E)-(1S,3R)-1,3-dihydroxy-24-(thien-2-yl)-9,10-secochola-5,7,10(19)-trien-24-one

[0163](5Z,7E)-(1S,3R,24S)-24-(4-methylthien-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol

[0164](5Z,7E)-(1S,3R,24R)-24-(4-methylthien-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol

[0165](5Z,7E)-(1S,3R)-1,3-dihydroxy-24-(4-methylthien-2-yl)-9,10-secochola-5,7,10(19)-trien-24-one

[0166](7E)-(1R,3R,24aR)-24a-fluoro-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3-diol

[0167](7E)-(1R,3R,24aS)-24a-fluoro-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3-diol

[0168](5Z,7E)-(1S,3R,24aR)-24a-fluoro-24a-(thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3-diol

[0169](5Z,7E)-(1S,3R,24aS)-24a-fluoro-24a-(thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3-diol

[0170](7E)-(1R,3R,24aR)-24a-(acetyloxy)-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0171](7E)-(1R,3R,24aS)-24a-(acetyloxy)-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0172](7E)-(1R,3R,24aR)-24a-(2,2-dimethylpropanoyloxy)-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0173](7E)-(1R,3R,24aS)-24a-(2,2-dimethylpropanoyloxy)-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0174](7E)-(1R,3R)-2-bromo-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol.

[0175] The substances according to the invention have a considerablyhigher metabolic stability than the structurally related compounds ofthe prior art and are therefore suitable in a special way for systemicadministrations.

[0176] Relative to the structurally related compounds of the prior art,some of the substances according to the invention are also characterizedin that they show a stronger action on cell differentiation, whereby theaction on the calcium balance does not increase.

[0177] Others of the substances according to the invention, however,exhibit an antagonistic or partial agonistic profile of action, whichmakes possible new uses.

[0178] Determination of Biological Activity

[0179] The vitamin D activity of the substances according to theinvention is determined with the aid of the calcitriol-receptor test. Itis carried out using a protein extract from the intestines of juvenilepigs. Receptor-containing protein extract is incubated in a test tubewith ³H-calcitriol (5×10¹⁰ mol/l) in a reaction volume of 0.27 ml in theabsence and in the presence of test substances for two hours at 4° C. Toseparate free and receptor-bound calcitriol, a charcoal-dextranabsorption is carried out. To this end, 250 μl of a charcoal-dextransuspension is fed to each test tube and incubated at 4° C. for 20minutes. Then, the samples are centrifuged at 10,000 g for 5 minutes at4° C. The supernatant is decanted and measured in a B-counter after 1hour of equilibration in Picofluor 15™.

[0180] The competition curves that are obtained at variousconcentrations of test substance as well as of reference substance(unlabeled calcitriol) at constant concentration of the referencesubstance (³H-calcitriol) are placed in relation to one another, and acompetition factor (KF) is determined.

[0181] It is defined as a quotient of the concentrations of therespective test substance and the reference substance, which arenecessary for 50% competition:${KF} = \frac{{concentration}\quad {of}\quad {test}\quad {substance}\quad {at}\quad 50\% \quad {competition}}{{concentration}\quad {of}\quad {reference}\quad {substance}\quad {at}\quad 50\% \quad {competition}}$

[0182] To determine the acute hypercalcemic action of various calcitriolderivatives, the test that is described below is carried out:

[0183] The action of control (solution base), reference substance(1,25-dihydroxy vitamin D₃=calcitriol) and test substance is tested ineach case after one-time subcutaneous administration in groups of 10healthy male rats (140-170 g). During the testing time, the rats arekept in special cages to determine the excretion of water and mineralsubstances. Urine is collected in 2 fractions (0-16 hours and 16-22hours). An oral dose of calcium (0.1 mmol of calcium in 6.5%alpha-hydroxypropyl-cellulose, 5 ml/animal) replaces at 1600 hours thecalcium intake that is lacking by food deprivation. At the end of thetest, the animals are killed by decapitation and exsanguinated todetermine the serum-calcium values. For the primary screen test in vivo,an individual standard dose (200 μg/kg) is tested. For selectedsubstances, the result is supported by establishing a dose-effectrelation.

[0184] A hypercalcemic action is shown in serum-calcium level valuesthat are higher than in the control.

[0185] The significance of differences occurring between substancegroups and controls and between test substance and reference substanceare supported with suitable statistical processes. The result isindicated as dose ratio DR (DR=factor of test substance dose/referencesubstance dose for comparable actions).

[0186] The differentiation-stimulating action of calcitriol analogues isalso detected quantitatively.

[0187] It is known in the literature [D. J. Mangelsdorf et al., J. Cell.Biol. 98: 391 (1984)] that the treatment of human leukemia cells(promyelocyte cell line HL 60) in vitro with calcitriol induces thedifferentiation of cells to macrophages.

[0188] HL 60 cells are cultivated in tissue culture medium (RPMI 10%fetal calf serum) at 37° C. in an atmosphere of 5% CO₂ in air.

[0189] For substance testing, the cells are centrifuged off, and 2.0×10⁵cells/ml in phenol red-free tissue culture medium is taken up. The testsubstances are dissolved in ethanol and diluted with tissue culturemedium without phenol red to the desired concentration. The dilutionstages are mixed with the cell suspension at a ratio of 1:10, and 100 μleach of this cell suspension that is mixed with substance is pipettedinto an indentation of a 96-hole plate. For control, a cell suspensionis mixed analogously with the solvent.

[0190] After incubation for 96 hours at 37° C. in 5% CO₂ in air, 100 μlof an NBT-TPA solution (nitro blue tetrazolium (NBT), finalconcentration in the batch of 1 mg/ml, tetradecanoylphorbolmyristate-13-acetate (TPA), final concentration in the batch of2×10⁻⁷ mol/l) is pipetted into each indentation of the 96-hole-plate inthe cell suspension.

[0191] By incubation for 2 hours at 37° C. and 5% CO₂ in air, NBT isreduced to insoluble formazan because of the intracellular oxygenradical release, stimulated by TPA, in the cells that are differentiatedto macrophages.

[0192] To complete the reaction, the indentations of the 96-hole plateare suctioned off, and the cells are affixed to the bottom of the plateby adding methanol and dried after affixing. To dissolve theintracellular formazan crystals that are formed, 100 μl of potassiumhydroxide (2 mol/l) and 100 μl of dimethyl sulfoxide are pipetted intoeach indentation and ultrasonically treated for 1 minute. Theconcentration of formazan is measured by spectrophotometry at 650 nm.

[0193] As a yardstick for the differentiation induction of HL 60 cellsto macrophages, the concentration of formed formazan applies. The resultis indicated as a dose ratio (DR=factor of test substance dose/referencesubstance dose for comparable semi-maximum actions).

[0194] The results of the calcitriol-receptor test and the determinationof the dose ratio of the differentiation induction of HL 60 cells andthe dose ratio for hypercalcemia are summarized below:

[0195] Examples of Test Substances:

[0196](7E)-(1R,3R,2aR)-24a-(Oxazol-4-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol16a

[0197](5Z,7E)-(1S,3R,24aR)-24a-(oxazol-4-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol20a

[0198](7E)-(1R,3R,24aS)-24a-(thien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol55b

[0199](7E)-(1R,3R)-1,3-dihydroxy-24a-(thien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one57

[0200](5Z,7E)-(1S,3R,24R)-24-(thiazol-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol217a KF DR (HL 60) DR (Ca) 16a 5 5 >30 20a 3 2 >50 55b 5 8 >100 57 122 >350 217a 7 100 >300 Calcitriol 1 1 1

[0201] In addition to a considerable affinity to the vitamin D receptor,the compounds listed show a pronounced cell-differentiating activity.

[0202] The induction of a hypercalcemia is carried out, however, only atvery much higher doses than in the case of calcitriol.

[0203] By the reduced property of triggering a hypercalcemia as well asthe high metabolic stability, the substances according to the inventionare suitable in a special way for the production of pharmaceuticalagents for the treatment of diseases that are characterized byhyperproliferation and deficient cell differentiation. Included in theseare, for example, hyperproliferative diseases of the skin (psoriasis,pityriasis subia pilasis, acne, ichthyosis) and pruritus, as well astumor diseases and precancerous stages (for example, tumors of theintestines, carcinomas of the breast, lung tumors, prostate carcinomas,leukemias, T-cell lymphomas, melanomas, Betazell carcinoma, squamouscarcinoma, actinic keratoses, cervix dysplasias, and metastasizingtumors of any type).

[0204] Also, for the treatment and prophylaxis of diseases that arecharacterized by a disequilibrium of the immune system, the substancesaccording to the invention are suitable. These include eczemas anddiseases of the atopic Formon series and inflammatory diseases(rheumatoid arthritis, respiratory tract diseases, e.g., asthma), aswell as auto-immune diseases, such as, for example, multiple sclerosis,diabetes mellitus type I, myasthenia gravis, lupus erythematosus,scleroderma, bullous skin diseases (pemphigus, pemphigoid), furtherrejection reactions in the case of autologous, allogeneic or xenogeneictransplants, as well as AIDS. In all of these diseases, the newcompounds of general formula I can be combined advantageously with othersubstances that have an immunosuppressive action, such as cyclosporin A,FK 506, rapamycin and anti-CD 4-antibodies.

[0205] The substances are also suitable for therapy of secondaryhyperparathyroidism and renal osteodystrophia because of the property ofcalcitriols to drop the parathormone synthesis.

[0206] Owing to the presence of the vitamin D receptor in theinsulin-producing cells of the pancreas, the substances are suitable byincreasing the insulin secretion for the therapy of diabetes mellitustype II.

[0207] Further, it has been found, surprisingly enough, that by topicalapplication of the compounds according to the invention on the skin ofmice, rats and guinea pigs, an increased reddening of the skin andincrease of the thickness of the epidermis can be induced. The increasein the reddening of the skin is-determined based on the increase in thered value of the skin surface that can be quantified with a colorimeter.The red value is typically increased 1.5-fold after the substance (dose0.003%) is administered three times at intervals of 24 hours. Theincrease in the thickness of the epidermis is quantified in thehistological preparation. It is typically increased 2.5-fold. The numberof proliferating epidermal cells (cells in the S-phase of the cellcycle) is determined by flow cytometry and is typically increased by afactor of 6.

[0208] These properties of the derivatives in the vitamin D seriesaccording to the invention can appear suitable for therapeutic use inthe case of atrophic skin, as it occurs in natural skin aging because ofincreased light exposure or medicinally-induced skin atrophy bytreatment with glucocorticoids.

[0209] Further, it can be assumed that wound healing can be acceleratedby topical application with the new compounds.

[0210] In cell populations of the hair follicle, which contributedecisively to hair growth or to hair cycle regulation, it was possibleto detect vitamin D₃ receptor proteins [W. E. Stumpf et al., Cell TissueRes. 238, 489 (1984); P. Milde et al., J. Invest. Dermatol. 97, 230(1991)]. In addition, in vitro findings on isolated hair folliclekeratinocytes show a proliferation-inhibiting anddifferentiation-stimulating influence of 1,25-(OH)₂-D₃.

[0211] From clinical observations, it is known that the vitaminD₃-resistant rickets often accompanies alopecia, which develops in earlyinfancy. Experimental findings show that the vitamin D₃-bonding site ofthe VDR in this disease mutates, i.e., is defective [K. Kristjansson etal., J. Clin. Invest. 92, 12 (1993)]. Keratinocytes, which were isolatedfrom the hair follicles of these patients, do not react in vitro to theaddition of 1,25-(OH)₂D₃ [S. Arase et al., J. Dermatol. Science 2, 353(1991)].

[0212] These findings indicate a decisive role for 1,25-(OH)₂D₃ in theregulation of hair growth.

[0213] These analogues are therefore especially suitable for theproduction of pharmaceutical agents for the treatment of diseases whichaccompany disrupted hair growth (androgenetic alopecia, alopeciaareata/totalis, chemotherapy-induced alopecia) or for supportingphysiological hair growth without causing the side-effects of calcitriol(especially hypercalcemia).

[0214] Senile and postmenopausal osteoporosis is characterized by anincreased bone turnover with an overall negative balance. Owing to thebone shrinkage especially of trabecular bones, fractures result to anincreased extent. Owing to the stimulating action of calcitriol, both inthe number and the conduct of synthesis of cells forming new bones(osteoblasts), the substances according to the invention are suitablefor therapy and prophylaxis of senile and postmenopausal osteoporosis(EP 0 634 173 A1), of steroid-induced osteoporosis as well as foraccelerated healing of arthroplasties without causing the side-effectsof calcitriol (especially hypercalcemia). For the therapy of variousforms of osteoporosis, they can be combined advantageously withestradiol or other derivatives of estrogen.

[0215] Finally, it was possible to show that calcitriol increases thesynthesis of a growth substance for nerve cells (nerve growth factor)[M. S. Saporito et al. Brain Res. 633, 189 (1994)]. The compoundsaccording to the invention are therefore also suitable for treatingdegenerative diseases of the peripheral and central nervous system, suchas Alzheimer's disease and amyotrophic lateral sclerosis.

[0216] In addition, it has been found that certain compounds of generalformula I in HL 60 cells antagonize, surprisingly enough, the action ofcalcitriol.

[0217] Such compounds can be used for the therapy of hypercalcemias,such as, for example, in hypervitaminosis D or intoxication withcalcitriol and calcitriol-like active substances, or in the case ofincreased extrarenal calcitriol synthesis in granulomatous diseases(sarcoidosis, tuberculosis). Also, paraneoplastic hypercalcemias (forexample, in osteolytic metastases and tumors with increased synthesis ofparathormone-related peptides) as well as in hypercalcemias in the caseof hyperparathyroidism.

[0218] In addition, calcitriol antagonists can be used for birthcontrol. In the reproductive tracts of female and male animals, thevitamin D receptor is expressed. It is known that the female and-malefertility of vitamin-D-deficient animals is reduced. By short-termsubstitution of calcitriol, the reproductive output can be increased.Calcitriol antagonists are therefore able to influence female and malefertility.

[0219] Since calcitriol, under certain conditions, shows animmunosuppressive action, calcitriol receptor antagonists can also beused as immunostimulants, e.g., in the case of weak defenses againstinfections, AIDS.

[0220] Calcitriol is known to be able to modulate hair growth.Calcitriol antagonists can therefore be used therapeutically in the caseof undesirable hair growth, e.g., in hirsutism.

[0221] Vitamin D has long been known to play a stimulating role in theformation of arteriosclerotic plaque. In such vascular lesions, acalcitriol-regulated protein, osteopontin, is found to be increased, towhich a role in vascular sclerosis is attributed [R. Eisenstein et al.Arch. Path. 77, 27 (1964), L. A. Fitzpatrick et al., J. Clin. Invest.94, 1597 (1994)]. Calcitriol antagonists are therefore suitable fortherapy and prophylaxis of all types of arteriosclerosis.

[0222] Finally, calcitriol antagonists are suitable because of theproperty of calcitriol to increase unspecific immune reactions ofmonocytic cells, for therapy of inflammatory diseases, especially of achronic nature, such as rheumatoid arthritis, Crohn's disease,ulcerative colitis, and granulomatous diseases such as sarcoidosis andother foreign-body reactions.

[0223] For all listed therapeutic applications, it is true that thecompounds according to the invention are able to achieve a therapeuticaction in the above-mentioned clinical pictures without causing theside-effects of calcitriol (especially hypercalcemia).

[0224] This invention thus relates to pharmaceutical preparations thatcontain at least one compound according to general formula I togetherwith a pharmaceutically compatible vehicle.

[0225] The compounds can be formulated as solutions in pharmaceuticallycompatible solvents or as emulsions, suspensions or dispersions insuitable pharmaceutical solvents or vehicles or as pills, tablets orcapsules, which contain solid vehicles in a way known in the art.

[0226] For topical use, the compounds are advantageously formulated ascreams or ointments or in a similar form of pharmaceutical agent that issuitable for topical use. Each such formulation can also contain otherpharmaceutically compatible and nontoxic adjuvants, such as, e.g.,stabilizers, antioxidants, binders, dyes, emulsifiers or flavoringadditives.

[0227] The compounds are advantageously administered by injection,intravenous infusion of suitable sterile solutions, as an aerosol viabronchial tubes and lungs, or as oral dosage via the alimentary tract ortopically in the form of creams, ointments, lotions or suitabletransdermal patches, as is described in EP-A 0 387 077.

[0228] The daily dose is approximately 0.1 μg/patient/day-1000μg/patient/day,

[0229] preferably 1.0 μg/patient/day-500 μg/patient/day.

[0230] Process for the Production of the Compounds According to theInvention

[0231] The production of the vitamin D derivatives of general formula Iis carried out according to the invention from a compound of generalformula II,

[0232] in which Y′₁ and Y′₂ mean hydroxy protective groups, and Y′₃ is ahydrogen atom, a halogen atom or a protected hydroxy group.

[0233] X′₁, X′₂ and Z′ are distinguished from X₁, X₂ and Z in thatoptionally present hydroxy groups or keto groups can be present inprotected form.

[0234] The protective groups are preferably alkyl-, aryl- or mixedalkylaryl-substituted silyl groups, e.g., the trimethylsilyl (TMS),triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS),tert-butyldiphenylsilyl (TBDPS) or triisopropylsilyl (TIPS) groups oranother standard hydroxy protective group (trimethylsilylethoxymethyl,methoxymethyl, methoxyethoxymethyl, ethoxyethyl, tetrahydrofuranyl andtetrahydropyranyl groups) as well as acetyl, propionyl or pivaloylgroups; for the keto groups, these are preferably ketals (1,3-dioxolans,1,3-dioxanes, dialkoxyketals) (see T. W. Greene, P. G. M. Wuts“Protective Groups in Organic Synthesis,” 2^(nd) Edition, John Wiley &Sons, 1991).

[0235] By simultaneous or successive cleavage of the hydroxy and ketoprotective groups and optionally by partial, successive or completeesterification of the free hydroxyl groups, the compound of generalformula II is converted into a compound of general formula I.

[0236] In the case of the silyl protective groups or thetrimethylsilylethoxymethyl group, tetrabutylammonium fluoride,hydrofluoric acid or hydrofluoric acid/pyridine or acidic ion exchangeris used for their cleavage. In the case of the ether groups(methoxymethyl, methoxyethoxymethyl, ethoxyethyl, tetrahydropyranylether) and ketals, the latter are cleaved off under catalytic action ofacid, for example, p-toluenesulfonic acid,pyridinium-p-toluenesulfonate, acetic acid, hydrochloric acid,phosphoric acid or an acidic ion exchanger. Ester groups, however, arehydrolyzed in a basic medium (sodium carbonate, potassium carbonate,sodium hydroxide, potassium hydroxide in water, ethanol, methanol ormixtures of these solvents).

[0237] The esterification of the free hydroxy groups can be carried out,if desired, according to standard processes with the correspondingcarboxylic acid chlorides, bromides or -anhydrides.

[0238] The production of the starting compounds for general formula II,in which Q means at least one ethylene group, starts from variousstarting compounds depending on the ultimately desired substitutionpattern in 20-position. For the compounds with natural configuration atC-20, the known CD-fragment III is used as starting material [H. H.Inhoffen, G. Quinkert, S. Schutz, G. Friedrich, E. Tober Chem. Ber. 91,781-791 (1958)].

[0239] By introduction of a protective group, the compound of generalformula IV

[0240] is obtained, whereby Y₄, i.a., can mean a trialkyl-substituted ora mixed arylalkyl-substituted silyl group or a tetrapyranyl ortetrafuranyl group. Ozonolytic cleavage of the side-chain double bondfollowed by reductive working-up (e.g., sodium borohydride) yields thecompound of general formula V.

[0241] The free hydroxy group can now be converted into a leaving group,whereby the compound of general formula VI is produced,

[0242] for which the following is true:. L stands for any leaving group,especially for a halogen atom (fluorine, chlorine, bromine, iodine) or amesylate, tosylate, triflate or nonaflate.

[0243] Via the propargyl alcohol VII and the conversion into alcoholVIII and oxidation to aldehyde IX described below, the compound offormula VI opens up a new, not yet known access to ketone XIII furtherdescribed below that represents an important starting material for thesynthesis of vitamin D derivatives according to De Luca [H. F. DeLuca etal. Tetrahedron Lett. 32, 7663 (1991); H. F. DeLuca et al. J. Med. Chem.37, 3730 (1994)].

[0244] This invention thus also relates to a process for the productionof ketone XIII via the new intermediate stages of Formulas VII, VIII andIX. The synthesis method can be modified in any way desired for anotherchain length, by a corresponding protected alkinol being used. By way ofexample, the synthesis method for a compound in which Q means anethylene group is described below.

[0245] Reaction of the compound of general formula VI with a protectedpropargyl alcohol, which was previously deprotonated with a base (e.g.,sodium hydride, potassium hydride, butyllithium, sodium amide), yieldsthe compound of general formula VII

[0246] for which the following is true: Y₅ is to represent atetrahydropyranyl group, a benzyl group or a used protective group.Hydrogenation of the triple bond and the benzyl ether or optionallyfollowed by cleavage of the tetrahydropyranyl ether under the action ofacid (p-toluenesulfonic acid, pyridinium-p-toluenesulfonate, aceticacid, dimethyl aluminum chloride, methylaluminum dichloride, etc.) nowproduces the compound of general formula VIII, whose free hydroxy groupis converted with an oxidizing agent (pyridinium chlorochromate,pyridinium dichromate, Swern conditions, Collins conditions) into thealdehyde of general formula IX.

[0247] By reaction with any nucleophile Nu, which can be brought toreaction with the aldehyde, such as, e.g., anions, optionally organicradicals that contain oxygen or sulfur atoms, optionally substitutedGrignard reagents that are optionally protected on sensitive functionalgroups, or lithium compounds, which can be produced according to methodsthat are known in the literature, a compound of general formula Xa isobtained as a mixture of the diastereomeric alcohols.

[0248] For the synthesis of the compounds according to the invention,the compound of general formula X

[0249] is obtained by reaction with a nucleophilic form of Z with thedesignation Z′, preferably with a metalated aromatic or heteroaromaticcompound.

[0250] Z can be any of the radicals that are defined for Z, preferablyfuran, thiophene, oxazole, thiazole, imidazole, pyrazole, pyrrole,benzofuran, benzothiophene, benzoxazole, benzothiazole, benzimidazole,indole or phenyl, whereby the rings can carry one or more substituentsat any positions. As substituents, there are fluorine, chlorine, bromineor iodine atoms, one or more hydroxy groups, one or more COOR₆ groups,one or more C₁-C₅ alkyl groups, which in turn can be substituted by oneor more fluorine, chlorine, bromine or iodine atoms, C₁-C₆ alkoxy groupsand/or COOR₆ groups (and R₆ is defined as a C₁-C₆ alkyl group, a benzylgroup or a phenyl group). The aromatic compounds are converted into themetalated derivatives by hydrogen-lithium exchange, orthometalation,halogen-lithium exchange (use of n-butyllithium, s-butyllithium,t-butyllithium, methyllithium) or reaction of halogen compounds withmagnesium or zinc. The linkage to the CD-fragment is always carried outin the metalated position with the exception of oxazole rings, whichhook on by rearrangement and recycling at the 4-position [G. Boche etal. Chem. Ber./Receuil 130, 1213 (1997)].

[0251] Conversion of the free hydroxy group into acetate groupings(R′=Me), propionate groupings (R′=Et) or pivalate groupings (R′=t-Bu)produces compounds of general formula XI, and it is converted into acompound of general formula XII by cleavage of cyclohexanol protectivegroups Y₄. If Y₄ means a silyl group, its cleavage can be carried out,e.g., with use of tetrabutylammonium fluoride, hydrogen fluoride,hydrogen fluoride/pyridine complex; however, if Y₄ means atetrahydropyranyl group or a tetrahydrofuranyl group, its cleavage canbe completed under acidic conditions. Subsequent oxidation of the freehydroxy group with an oxidizing agent (pyridinium chlorochromate,pyridinium dichromate, Swern conditions, Collins conditions) yields thecompound of general formula XIII.

[0252] Reaction of the ketone of general formula XIII with one of theknown phosphine oxides XIV, XV or XVI [XIV: M. R. Uskokovic et al.Tetrahedron Lett. 33, 7701 (1992), A. Mourino et al. Tetrahedron Lett.38, 4713 (1997), XV: H. F. DeLuca et al. Tetrahedron Lett. 32, 7663(1991), XVI: H. F. DeLuca et al. J. Med. Chem. 37, 3730 (1994)],

[0253] whereby Y′₁ and Y′₂ represent alkyl- or mixedarylalkyl-substituted silyl groups (preferably tert-butyldimethylsilyl,tert-butyldiphenylsilyl, trimethylsilyl, triethylsilyl andtriisopropylsilyl groups) and Y′₃ means the corresponding silyloxygrouping, yields the vitamin D systems of general formulas XVII, XVIIIand XIX.

[0254] The compounds of general formulas XVII, XVIII and XIX representspecial cases of general formula II and are converted into compounds ofgeneral formula I as described above.

[0255] In particular, the hydroxy group in position C-24 can be releasedand converted with an oxidizing agent (e.g., pyridinium chlorochromate,pyridinium dichromate, Collins reagent, Swern conditions, manganesedioxide) into the corresponding ketone, which likewise represents aspecial case of general formula II. The C-24 alcohols or the C-24 ketonecan be converted into halides or dihalides under known conditions. Thepossibility of the reductive removal of the hydroxy, keto or halogenunits also exists.

[0256] Any manipulations of the functional groups in the side chain canalso be completed in earlier stages.

[0257] For the production of compounds of general formula II withaltered substitution patterns at C-20, the alcohol of general formula Vis oxidized to the aldehyde of general formula XX with an oxidizingagent (e.g., pyridinium chlorochromate, pyridinium dichromate, Collinsreagent, Swern conditions, Dess-Martin conditions). The latter can beconverted as described [DE 42 20 757, 20-epi: M. J. Calverley Bioorg.Med. Chem. Lett. 3, 1845 (1993)] into compounds of general formula XXI,in which R₃ and R₄ have the already-mentioned meanings. Then, thereduction with a reducing agent (e.g., sodium borohydride, lithiumaluminum hydride, diisobutylaluminum hydride) is carried out to alcoholof general formula XXII, which is further reacted as described above.

[0258] For compounds of general formula II, the following is true: Q isa methylene group, and a start is made from known vitamin D-aldehydeXXIII, which can be modified at position 20 as described above (DE 19619 036). By way of example, the further reaction of aldehyde withnatural configuration at C-20 is described.

[0259] With a reducing agent (e.g., sodium borohydride, lithium aluminumhydride, isobutylaluminum hydride), the alcohol of general formula XXIV,which is converted into a leaving group as described above, is obtained,whereby the compound of general formula XXV accumulates.

[0260] Reaction of the compounds of general formula XXV with theacetonitrile that is deprotonated by a base (e.g., lithiumdiisopropylamide, sodium hexamethyldisilazide, lithium hexamethyldisilazide, potassium hexamethyl disilazide) produces a compound ofgeneral formula XXVI, which is converted by reduction with a reducingagent (e.g., diisobutylaluminium hydride) into a compound of generalformula XXVII.

[0261] By reaction with the nucleophile of a carbocyclic or heterocycliccompound, preferably a metalated aromatic or heteroaromatic compound,compounds of general formula XXVIII

[0262] as already shown above, which are to be considered as a specialcase of general formula II, are obtained and are to be converted intocompounds of general formula I as described. In particular, the hydroxygroup in position C-24 can be converted into the corresponding ketonewith an oxidizing agent (e.g., pyridinium chlorochromate, pyridiniumdichromate, Collins reagent, Swern conditions, manganese dioxide), whichlikewise represents a special case of general formula II. The C-24alcohols or the C-24 ketone can be converted into halides or dihalidesunder known conditions. The possibility also exists of the reductiveremoval of hydroxy, keto or halogen units.

[0263] If compounds of general formula I are to be generated, for whichY₃ is a halogen atom (e.g., fluorine, chlorine or bromine atom), anA-component of general formula XXX, whereby Y₃ is to have theabove-mentioned meaning, must by synthesized from the cyclohexanederivative XXIX that is known from the literature [J. -L. Montchamp, J.W. Frost J. Am. Chem. Soc. 113, 6296 (1991)] by Hanessian reaction.

[0264] Introduction of a protective group for the free hydroxy groupproduces the compound of general formula XXXI, which is converted in theacid medium as usual into diol XXXII and by subsequent diol cleavage(sodium periodate, periodic acid) into ketone XXXIII, whereby thedefinitions for Y′₁ and Y₃ were already indicated.

[0265] In building the vitamin D system, a new approach is used forY₃=halogen, which can also be used, however, for all possiblesubstituents for Y₃ (also Y₃=a hydrogen atom), as well as for othersubstitution patterns in the A-ring (e.g., instead of OY₁ in 1-position,halogen, (CH₂)_(n)—OH or (CH₂)_(n)—O(CO)R₅ with R=aliphatic C₁-C₁₂ alkylradical, which optionally is interrupted by 1-2 oxygen atoms, 1-2 sulfuratoms and/or 1-2 NH groups and/or optionally is substituted by 1-2hydroxy groups, 1-2 amino groups, 1-2 SH groups, 1-2 COOH groups and/or1-2 phenyl groups, with n=0-4 or an aromatic radical with 5 to 12 Catoms), and also any side chains in 17-position with optionallyprotected existing hydroxy groups and/or keto groups.

[0266] The reactions at the ketone of general formula XIII are describedhere by way of example but are also valid for other side-chain variants:

[0267] By Peterson olefination (reaction with trimethylsilylacetic esterin the presence of a base, such as, e.g., n-butyllithium or lithiumdiisopropylamide), the compound of general formula XXXIV, whose estergroup is converted into the alcohol of general formula XXXV by reductionwith a reducing agent (e.g., diisobutylaluminum hydride, lithiumaluminum hydride) is obtained from ketone XIII. The conversion of thehydroxy group into a diphenylphosphine oxide derivative of generalformula XXXVI is carried out according to standard conditions via anallyl halide (chloride, bromide) or an intermediate tosylate ormesylate.

[0268] The linkage with the ketone of general formula XXXIII ultimatelyproduces the vitamin D system of general formula II with the alreadymentioned definitions for Y₃. The conversion into a compound of generalformula I is carried out as described previously by cleavage of theprotective groups.

[0269] The subject of this invention is thus also a new process for theproduction of vitamin D derivatives of general formula IIa,

[0270] in which.

[0271] E means any side chain,

[0272] R₇, R₈, independently of one another, mean a hydrogen atom, amethyl group, or together an exocyclic methylene group or a cyclopropylring,

[0273] Y₂ means a hydrogen atom or a group —(CO)R₅,

[0274] Y₃ means a hydrogen atom, a hydroxy group, a halogen atom, agroup —O(CO)R₅ or an OR₅ group,

[0275] whereby

[0276] R₅ stands for an aliphatic C₁-C₁ alkyl radical, which optionallyis interrupted by 1-2 oxygen atoms, 1-2 sulfur atoms and/or 1-2 NHgroups and/or optionally is substituted by 1-2 hydroxy groups, 1-2 aminogroups, 1-2 SH groups, 1-2 COOH groups and/or 1-2 phenyl groups, or foran aromatic radical with 5 to 12 C atoms,

[0277] Y₅ means a fluorine atom, a (CH₂)_(n)—OH group or a(CH₂)_(n)—O(CO)R₅ group,

[0278] whereby n=0 to 4,

[0279] and optionally present hydroxy groups are optionally present inprotected form, which is characterized in that a ketone of generalformula XIIIc

[0280] in which

[0281] E means any side chain.

[0282] and optionally existing keto groups and/or hydroxy groups arepresent in protected form

[0283] is converted by reaction with trimethylsilylacetic ester in thepresence of a base, such as, e.g., n-butyllithium or lithium aluminumhydride or with a suitable Wittig reagent in an aprotic solvent such astoluene, tetrahydrofuran, diethyl ether or dioxane into a compound ofgeneral formula XXXIVc

[0284] in which

[0285] Y₆ means a C₁-C₆ alkyl group, a benzyl group, or a phenyl group,

[0286] the ester group is converted by reaction with a reducing agentsuch as Dibah, lithium aluminum hydride, diborane or RedAl in hexane,toluene, tetrahydrofuran, diethyl ether or dioxane into the allylalcohol of general formula XXXVc

[0287] the allyl alcohol is converted in a way that is known in the artinto a compound of general formula XXXVc

[0288] in which

[0289] L means any leaving group (halogen, mesylate, tosylate, triflate,nonaflate),

[0290] which is isolated or optionally produced in situ and immediatelyfurther reacted to a Wittig reagent of general formula XXXVIc,

[0291] in which

[0292] G means a C₁-C₁₀ alkyl group, a C₁-C₁₀ alkoxy group, a phenylradical or a phenoxy radical,

[0293] which then is reacted under known conditions with a ketone ofgeneral formula XXXIIIc

[0294] in which

[0295] Y′₃ means a hydrogen atom, a halogen atom or a protected hydroxygroup, a group —O(CO)R₅ or an OR₅ group, and Y₅, R₇ and R₈ have theabove-indicated meaning,

[0296] and if desired, protective groups are cleaved.

[0297] The compounds of general formula IIa can be converted into thedesired vitamin D derivatives-by cleavage of the protective groups asdescribed above.

[0298] Especially suitable is the process according to the invention forthe production of vitamin D derivatives, in which Y₃ means a halogenatom, but it is not limited thereto.

[0299] The additives “a” in the designation of the formulas (e.g.,XXXIVa) is to make clear that the meanings of the radicals are basicallythe same as in the formula without additive “a”, but sensitive groupsare present in protected form.

[0300] An alternative method to the synthesis of compounds of generalformula II, for which X′₁ and X′₂ mean hydrogen atoms and Q representsan ethylene group, starts from alcohol of general formula VIII, whosehydroxy group is converted into a leaving group (e.g., chloride,bromide, iodide, tosylate, mesylate) and is reacted with metalatedaromatic or heteroaromatic compounds, whereby compounds of generalformula XXXVII accumulate,

[0301] and whose further reaction can be carried out analogously to theabove-described compounds.

[0302] The examples below are used for a more detailed explanation ofthe invention.

EXAMPLES

[0303] Synthesis of the Starting Compounds (CD-Aldehyde):

[0304] 1.[1R-[1α[1R*,4S*-(E),3aβ,4α,7aα-Octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1-(1,4,5-trimethyl-2-hexenyl)-1H-indene2

[0305] 12.95 g of[1R-[1α[1R*,4S*-(E)],3aβ,4α,7aα]]-octahydro-7a-methyl-1-(1,4,5-trimethyl-2-hexenyl)-1H-inden-4-ol1 is introduced into 220 ml of dimethylformamide [H. H. Inhoffen et al.Chem. Ber. 91, 781 (1958)], 5.33 g of imidazole and 10.78 ml ofchlorotriethylsilane are added, and it is stirred for 24 hours at roomtemperature. It is quenched with sodium chloride solution, extractedwith ethyl acetate, the organic phase is washed with sodium chloridesolution and dried on sodium sulfate. After the solvent is removed, theresidue is purified by chromatography on silica gel with ethylacetate/hexane, whereby 14.6 g of title compound 2 is obtained as acolorless oil.

[0306]¹H-NMR (CDCl₃): δ=0.58 ppm (q, 6H); 0.82 (d, 3H); 0.84 (d, 3H);0.93 (t, 9H); 0.96 (d, 3H); 0.97 (s, 3H); 0.98 (d, 3H); 4.05 (m, 1H);5.19 (m, 2H)

[0307] 2.[1R-[1α(S*),3aβ,4α,7aα]]-2-[Octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1H-inden-1-yl]-1-propanol3

[0308] 14.6 g of silylether 2 is dissolved in 300 ml of dichloromethaneand 150 ml of methanol, 14.8 ml of pyridine is added, and it is cooledto −78° C. At this temperature, ozone, which has been produced by anozone generator, is introduced until the solution is blue-colored.Excess ozone is expelled by oxygen passing through it, and then it ismixed with 1.61 g of sodium borohydride. It is heated to roomtemperature, and then the reaction mixture is poured intodichloromethane. The organic phase is washed with sodium chloridesolution, dried on sodium sulfate and concentrated by evaporation. Theresidue is chromatographed by chromatography on silica gel with ethylacetate/hexane, whereby 10.1 g of title compound 3 is obtained as acolorless oil.

[0309]¹H-NMR (CDCl₃): δ=0.57 ppm (q, 6H); 0.92 (s, 3H); 0.96 (t, 9H);1.02 (d, 3H); 3.38 (dd, 1H); 3.63 (d, 1H); 4.05 (m, 1H)

[0310] 3.[1R-[1α(S*),3aβ,4α,7aα]]-2-[Octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1H-inden-1-yl]propyl-(4-methylbenzenesulfonate)4

[0311] 9.1 g of alcohol 3 is dissolved in 135 ml of pyridine, cooled to0° C., and then 7.8 g of p-toluenesulfonyl chloride is added. It isstirred overnight at 0° C. and then carefully quenched with sodiumbicarbonate solution. It is extracted with ethyl acetate, the organicphase is washed with sodium chloride solution, dried on sodium sulfate,and the solvent is removed in a vacuum. The residue is chromatographedon silica gel with ethyl acetate/hexane, whereby 13.3 g of titlecompound 4 is obtained as a colorless oil.

[0312]¹H-NMR (CDCl₃): δ=0.56 ppm (q, 6H); 0.87 (s, 3H); 0.96 (t, 9H);0.97 (d, 3H); 2.47 (s, 3H); 3.80 (dd, 1H); 3.97 (d, 1H); 4.01 (m, 1H);7.35 (d, 2H); 7.80 (d, 2H)

[0313] 4.[1R-[1α(R*),3aβ,4α,7aα]]-Octahydro-7a-methyl-1-[5-[(tetrahydro-2H-pyran-2-yl)oxy]-1-methyl-3-pentinyl-4-[(triethylsilyl)oxy]-1H-indene5

[0314] 15.4 g of propargyl-THP-ether is introduced into 350 ml ofdioxane, and 43.8 ml of n-butyllithium (2.5 M in hexane) is carefullyadded in drops at 10-15° C. After one hour, 13.3 g of tosylate 4 in 100ml of dioxane is added in drops, and it is heated to boiling for 48hours. It is then quenched with sodium chloride solution, extracted withethyl acetate, the organic phase is washed with sodium chloride solutionand dried on sodium sulfate. After the solvent is removed, the residueis chromatographed on silica gel with ethyl acetate/hexane, whereby 12.1g of title compound 5 is obtained as a colorless oil.

[0315]¹H-NMR (CDCl₃): δ=0.57 ppm (q, 6H); 0.92 (s, 3H); 0.96 (t, 9H);1.06 (d, 3H); 3.56 (m, 1H); 3.88 (m, 1H); 4.04 (m, 1H); 4.29 (d, 2H);4.83 (m, 1H)

[0316] 5.[1R-[1α(R*),3aβ,4α,7aα]]-Octahydro-7a-methyl-1-5-[(tetrahydro-2H-pyran-2-yl)oxy]-1-methylpentyl-4-[(triethylsilyl)oxy]-1H-indene6

[0317] 12.6 g of alkine 5 is dissolved in 250 ml of ethyl acetate, 2.2 gof palladium/carbon (10%) and 5.06 g of sodium bicarbonate are added andhydrogenated under normal pressure in a hydrogenating apparatus. Whenhydrogen is no longer taken up, the batch is filtered on Celite andconcentrated by evaporation. The residue is chromatographed on silicagel with ethyl acetate/hexane, whereby 9.9 g of title compound 6 isobtained as a colorless oil.

[0318]¹H-NMR (CDCl₃): δ=0.56 ppm (q, 6H); 0.91 (s, 3H); 0.95 (t, 9H);0.97 (d, 3H); 3.38 (m, 1H); 3.51 (m, 1H); 3.70 (m, 1H); 3.88 (m, 1H);4.02 (m, 1H); 4.59 (m, 1H)

[0319] 6.[1R-[1α(R*),3aβ,4α,7aα]]-5-[(Octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1H-inden-1-yl]-1-hexanol7

[0320] 11.4 g of THP-ether 6 is introduced into 500 ml ofdichloromethane, and 50 ml of dimethylaluminum chloride solution isadded in drops. After 2 hours at room temperature, it is quenched withisopropanol/water (15:85), toluene is added, and it is stirredovernight. Then, it is suctioned off on Celite and concentrated byevaporation. The residue is chromatographed on silica gel with ethylacetate/hexane, whereby 6.2 g of title compound 7 is obtained as acolorless oil.

[0321]¹H-NMR (CDCl₃): δ=0.56 ppm (q, 6H); 0.90 (s, 3H); 0.95 (t, 9H);0.96 (d, 3H); 3.64 (m, 2H); 4.02 (m, 1H)

[0322] 7.[1R-[1α(R*),3aβ,4α,7aα]]-5-[Octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1H-inden-1-yl]hexanal8

[0323] 8.0 g of alcohol 7 is dissolved in 300 ml of dichloromethane, andthen 6.5 g of pyridinium chlorochromate is added. It is stirred for 2hours at room temperature. Then, diethyl ether is added, filtered onCelite and concentrated by evaporation. The residue is chromatographedon silica gel with ethyl acetate/hexane, whereby 6.2 g of title compound8 is obtained as a colorless oil.

[0324]¹H-NMR (CDCl₃): δ=0.57 ppm (q, 6H); 0.91 (s, 3H); 0.95 (t, 9H);0.96 (d, 3H); 4.02 (m, 1H); 9.75 (t, 1H)

Example 1

[0325](7E)-(1R,3R,24aR)-24a-(Oxazol-4-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol16a and(7E)-(1R,3R,24aS)-24a-(oxazol-4-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol16b

[0326] 8. 939 mg of oxazole is introduced into 20 ml of tetrahydrofuranand cooled to −78° C. Then, 5.44 ml of n-butyllithium (2.5 M in hexane)is added in drops, stirred for 20 more minutes, and then 500 mg ofaldehyde 8 in 5 ml of tetrahydrofuran is added. It is stirred overnight,whereby the mixture is heated to room temperature and then quenched withsodium chloride solution. It is extracted with ethyl acetate, theorganic phase is washed with sodium chloride solution, dried on sodiumsulfate, and the solvent is removed. The residue is chromatographed onsilica gel with ethyl acetate/hexane, whereby 234 mg of[1R[1α(1R*),3aβ,4α,7aα]]-α-[4-[octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1H-inden-1-yl]-pentyl]oxazole-4-methanol9 is obtained as a colorless oil.

[0327]¹H-NMR (CDCl₃): δ=0.57 ppm (q, 6H); 0.86 (d, 3H); 0.92 (s, 3H);0.99 (t, 9H); 4.02 (m, 1H); 4.70 (m, 1H); 7.60 (s, 1H); 7.90 (s, 1H)

[0328] 9. 361 mg of alcohol 9 is introduced into 8 ml ofdichloromethane, 0.17 ml of triethylamine, 0.12 ml of acetic acidanhydride and a spatula-tip full of dimethylaminopyridine are added, andit is stirred overnight at room temperature. Then, sodium chloridesolution is added, extracted with ethyl acetate, the organic phase iswashed with sodium bicarbonate solution and sodium chloride solution,dried on sodium sulfate and concentrated by evaporation. The residue ischromatographed on silica gel with ethyl acetate/hexane, whereby 296 mgof[1R[1α(1R*),3aβ,4α,7aα]]-5-[octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1H-inden-1-yl]-1-(oxazol-4-yl)hexyl-acetate10 is obtained as a colorless oil.

[0329]¹H-NMR (CDCl₃): δ=0.57 ppm (q, 6H); 0.86/0.87 (d, 3H); 0.90 (s,3H); 0.98 (t, 9H); 2.09 (s, 3H); 4.02 (m, 1H); 5.80 (t, 1H); 7.62 (s,1H); 7.86 (s, 1H)

[0330] 10. 281 mg of acetate 10 is introduced into 10 ml oftetrahydrofuran, 1 ml of hydrogen fluoride-pyridine complex is added,and it is stirred overnight at room temperature. Then, it is quenchedwith sodium bicarbonate solution, extracted with ethyl acetate, theorganic phase is washed with sodium chloride solution, dried on sodiumsulfate, and the solvent is removed. The residue is chromatographed onsilica gel with ethyl acetate/hexane, whereby 193 mg of[1R-[1α(1R*),3aβ,4α,7aα]]-1-[5-(acetyloxy)-1-methyl-5-(oxazol-4-yl)pentyl]octahydro-7a-methyl-1H-inden-4-ol11 is obtained as a colorless oil.

[0331]¹H-NMR (CDCl₃): δ=0.88/0.89 ppm (d, 3H); 0.91 (s, 3H); 2.09 (s,3H); 4.07 (m, 1H); 5.80 (t, 1H); 7.61 (s, 1H); 7.85 (s, 1H)

[0332] 11. 193 mg of alcohol 11 is introduced into 8 ml ofdichloromethane, 160 mg of pyridinium chlorochromate is added, and it isstirred for 1 hour at room temperature. Then, it is diluted with diethylether, filtered on Celite, and the solvent is removed. The residue ischromatographed on silica gel with ethyl acetate/hexane, whereby 160 mgof[1R-[1α(1R*),3aβ,7aα]]-1-[5-(acetyloxy)-1-methyl-5-(oxazol-4-yl)pentyl]octahydro-7a-methyl-4H-inden-4-on12 is obtained as a colorless oil.

[0333]¹H-NMR (CDCl₃): δ=0.61 ppm (s, 3H); 0.91/0.92 (d, 3H); 2.10 (s,3H); 4.07 (m, 1H); 5.80 (t, 1H); 7.62 (s, 1H); 7.85 (s, 1H)

[0334] 12. 461 mg of[2-[(3R-trans)-3,5-bis[[(1,1-dimethylethyl)dimethyl-silyl]oxy]cyclohexylidene]ethyl]-diphenylphosphineoxide 13 [H. F. DeLuca et al. Tetrahedron Lett. 32, 7663 (1991), A.Mourino et al. Tetrahedron Lett. 38, 4713 (1997)] is introduced into 8ml of tetrahydrofuran, and it is cooled to −78° C. At this temperature,0.39 ml of n-butyllithium solution (2.5 M in hexane) is added, and it isstirred for 10 minutes at −30° C. Then, 146 mg of ketone 12 in 4 ml oftetrahydrofuran is added in drops, and it is stirred for one more hour.It is quenched with sodium chloride solution, extracted with ethylacetate, the organic phase is washed with sodium chloride solution,dried on sodium sulfate and concentrated by evaporation. The residue ischromatographed on silica gel with ethyl acetate/hexane, whereby 180 mgof(7E)-(1R,3R)-24a-(acetyloxy)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-(oxazol-4-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene14 is obtained as a colorless foam.

[0335]¹H-NMR (CDCl₃): δ=0.06 ppm (s, 12H); 0.52 (s, 3H); 0.89 (s, 18H);0.90 (d, 3H); 2.09 (s, 3H); 4.08 (m, 2H); 5.80 (t, 1H); 5.81 (d, 1H);6.18 (d, 1H); 7.61 (s, 1H); 7.87 (s, 1H)

[0336] 13. 180 mg of acetate 14 is introduced into 8 ml of methanol, 140mg of potassium carbonate is added, and it is stirred for 1 hour at roomtemperature. Then, it is mixed with sodium chloride solution, extractedwith ethyl acetate, the organic phase is washed with sodium chloridesolution, dried on sodium sulfate, and the solvent is removed. Theresidue is chromatographed on silica gel with ethyl acetate/hexane,whereby 144 mg of(7E)-(1R,3R)-13-bis[((1,1-dimethylethyl)dimethylsilyl]oxy]-24a-(oxazol-4-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-ol15 is obtained as a colorless foam.

[0337]¹H-NMR (CD₂Cl₂): δ=0.06 ppm (s, 12H); 0.52 (s, 3H); 0.84 (s, 18H);0.91/0.92 (d, 3H); 4.07 (m, 2H); 4.62 (m, 1H); 5.80 (d, 1H); 6.14 (d,1H); 7.55 (s, 1H); 7.82 (s, 1H)

[0338] 14. 144 mg of alcohol 15 is introduced into 10 ml oftetrahydrofuran, 467 mg of tetrabutylammonium fluoride (hydrate) isadded, and it is stirred for 2 days at room temperature. Then, sodiumbicarbonate solution is added, extracted with ethyl acetate, the organicphase is washed with sodium chloride solution, dried on sodium sulfateand concentrated by evaporation. The residue is chromatographed onsilica gel with ethyl acetate/hexane, and then the diastereomers (interms of C-24a) are separated via HPLC, whereby 25 mg of title compound16a and 34 mg of title compound 16b accumulate as colorless foams.

[0339]¹H-NMR (CD₂Cl₂): 16a: δ=0.52 ppm (s, 3H); 0.89 (d, 3H); 3.98 (m,1H); 4.03 (m, 1H); 4.62 (m, 1H); 5.82 (d, 1H); 6.28 (d, 1H); 7.57 (s,1H); 7.84 (s, 1H)

[0340] 16b: δ=0.52 ppm (s, 3H); 0.90 (d, 3H); 3.98 (m, 1H); 4.03 (m,1H); 4.62 (m, 1H); 5.82 (d, 1H); 6.28 (d, 1H); 7.57 (s, 1H); 7.83 (s,1H)

Example 2

[0341](5Z,7E)-(1S,3R,24aR)-24a-(Oxazol-4-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol20a and(5Z,7E)-(1S,3R,24aS)-24a-(oxazol-4-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol20b

[0342] 15. 257 mg of(2-[[3S-(1Z,3α,5β)]-0.3,5-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2-methylenecyclohexylidene]ethyl]-diphenylphosphineoxide 17 [M. R. Uskokovic et al. Tetrahedron Let. 33, 7701 (1992)) isintroduced into 6 ml of tetrahydrofuran, and it is cooled to −78° C. Atthis temperature, 0.21 ml of n-butyllithium solution (2.5 M in hexane)is added, and it is stirred for 10 minutes at −30° C. Then, 80 mg ofketone 12 in 4 ml of tetrahydrofuran is added in drops and stirred forone more hour. It is quenched with sodium chloride solution, extractedwith ethyl acetate, the organic phase is washed with sodium chloridesolution, dried on sodium sulfate and concentrated by evaporation. Theresidue is chromatographed on silica gel with ethyl acetate/hexane,whereby 140 mg of(5Z,7E)-(1S,3R)-24a-(acetyloxy)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-(oxazol-4-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene18 is obtained as a colorless foam.

[0343]¹H-NMR (CDCl₃): δ=0.06 ppm (s, 12H); 0.52 (s, 3H); 0.90 (s, 18H);0.90 (d, 3H); 2.09 (s, 3H); 4.19 (m, 1H); 4.38 (m, 1H); 4.88 (s, 1H);5.19 (s, 1H); 5.81 (t, 1H); 6.02 (d, 1H); 6.23 (d, 1H); 7.62 (s, 1H);7.87 (s, 1H)

[0344] 16. 140 mg of acetate 18 is treated analogously to 13., and 120mg of(5Z,7E)-(1S,3R)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]-oxy]-24a-(oxazol-4-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-ol19 is obtained as a colorless foam.

[0345]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.52 (s, 3H); 0.89 (s, 18H);0.90 (d, 3H); 4.19 (m, 1H); 4.38 (m, 1H); 4.87 (s, 1H); 5.20 (s, 1H);5.81 (t, 1H); 6.02 (d, 1H); 6.25 (d, 1H); 7.60 (s, 1H); 7.88 (s, 1H)

[0346] 17. 120 mg of alcohol 19 is treated analogously to 14., and afterthe diastereomers (in terms of C-24a) are separated by HPLC, 14 mg oftitle compound 20a and 18 mg of title compound 20b are obtained ascolorless foams.

[0347]¹H-NMR (CD₂Cl₂): 20a: δ=0.53 ppm (s, 3H); 0.91 (d, 3H); 4.15 (m,1H); 4.36 (m, 1H); 4.63 (m, 1H); 4.94 (s, 1H); 5.26 (s, 1H); 6.01 (d,1H); 6.35 (d, 1H); 7.56 (s, 1H); 7.84 (s, 1H)

[0348] 20b: δ=0.53 ppm (s, 3H); 0.90 (d, 3H); 4.15 (m, 1H); 4.36 (m,1H); 4.63 (m, 1H); 4.93 (s, 1H); 5.26 (s, 1H); 6.01 (d, 1H); 6.35 (d,1H); 7.56 (s, 1H); 7.85 (s, 1H)

Example 3

[0349](7E)-(1R,3R,24aR)-24a-(Thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol27a and(7E)-(1R,3R,24aS)-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol27b

[0350] 18. 3.1 ml of 2-bromothiazole is introduced into 40 ml oftetrahydrofuran, and 13.8 ml of n-butyllithium solution (2.5 M inhexane) is added at −78° C. After 30 minutes at this temperature, 2.52 gof aldehyde 8 in 10 ml of tetrahydrofuran is added in drops, and it isstirred for one more hour. Then, it is quenched with sodium chloridesolution, extracted with ethyl acetate, the organic phase is washed withsodium chloride solution and dried on sodium sulfate. The solvent isremoved, and the residue is chromatographed on silica gel with ethylacetate/hexane, whereby 2.6 q of[1R-[1α(1R*),3aβ,4α,7aα]]-α-[4-[octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1H-inden-1-yl]pentyl]thiazole-2-methanol21 is obtained as a colorless oil.

[0351]¹H-NMR (CDCl₃): δ=0.57 ppm (q, 6H); 0.88 (d, 3H); 0.91 (s, 3H);0.97 (t, 9H); 4.02 (m, 1H); 5.01 (m, 1H); 7.30 (d, 1H); 7.71 (d, 1H)

[0352] 19. 948 mg of alcohol 21 is treated analogously to 9., and 824 mgof[1R-[1α(1R*),3aβ,4α,7aα]]-5-[octahydro-7a-methyl-4-[((triethylsilyl)oxy]-1H-inden-1-yl]-1-(thiazol-2-yl)hexyl-acetate22 is obtained as a colorless oil.

[0353]¹H-NMR (CDCl₃): δ=0.56 ppm (q, 6H); 0.87/0.88 (d, 3H); 0.90 (s,3H); 0.96 (t, 9H); 2.14 (s, 3H); 4.02 (m, 1H); 6.10 (t, 1H); 7.31 (d,1H); 7.78 (d, 1H)

[0354] 20. 824 mg of acetate 22 is treated analogously to 10., and 583mg of[1R-[1α(1R*),3aβ,4α,7aα]]-1-[5-(acetyloxy)-1-methyl-5-(thiazol-2-yl)pentyl]octahydro-7a-methyl-1H-inden-4-ol23 is obtained as a-colorless oil.

[0355]¹H-NMR (CDCl₃): δ=0.88/0.89 ppm (d, 3H); 0.93 (s, 3H); 2.18 (s,3H); 4.07 (m, 1H); 6.10 (t, 1H); 7.31 (d, 1H); 7.78 (d, 1H)

[0356] 21. 583 mg of alcohol 23 is treated analogously to 11., and 514mg of[1R-[1α(1R*),3aβ,7aα]]-1-(5-(acetyloxy)-1-methyl-5-(thiazol-2-yl)pentyl]octahydro-7a-methyl-4H-inden-4-one24 is obtained as a colorless oil.

[0357]¹H-NMR (CDCl₃): δ=0.56 ppm (s, 3H); 0.91/0.92 (d, 3H); 2.12 (s,3H); 6.10 (t, 1H); 7.31 (d, 1H); 7.78 (d, 1H)

[0358] 22. 1.39 g of phosphine oxide 13, which was deprotonated with1.16 ml of n-butyllithium solution (2.5 M in hexane), is reacted with460 mg of ketone 24 analogously to 12., and 672 mg of(7E)-(1R,3R)-24a-(acetyloxy)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene25 is obtained as a colorless foam.

[0359]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.53 (s, 3H); 0.89 (s, 18H);0.93 (d, 3H); 2.18 (s, 3H); 4.09 (m, 2H); 5.82 (d, 1H); 6.10 (t, 1H);6.18 (d, 1H); 7.31 (d, 1H); 7.78 (d, 1H)

[0360] 23. 672 mg of acetate 25 is reacted analogously to 13., and 526mg of(7E)-(1R,3R)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]-oxy]-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-ol26 is obtained as a colorless foam.

[0361]¹H-NMR (CD₂Cl₂): δ=0.04 ppm (s, 12H); 0.51 (s, 3H); 0.87 (s, 18H);0.92 (d, 3H); 4.07 (m, 2H); 4.95 (m, 1H); 5.81 (d, 1H); 6.15 (d, 1H);7.31 (d, 1H); 7.70 (d, 1H)

[0362] 24. 426 mg of alcohol 26 is treated analogously to 14., and afterthe diastereomers (in terms of C-24a) are separated on HPLC, 134 mg oftitle compound 27a and 149 mg of title compound 27b are obtained ascolorless foams.

[0363]¹H-NMR (CD₂Cl₂/CD₃OD): 27a: δ=0.50 ppm (s, 3H); 0.88 (d, 3H); 3.93(m, 1H); 4.01 (m, 1H); 4.90 (t, 1H); 5.83 (d, 1H); 6.23 (d, 1H); 7.29(d, 1H); 7.67 (d, 1H)

[0364] 27b: δ=0.50 ppm (s, 3H); 0.90 (dd, 3H); 3.93 (m, 1H); 4.01 (m,1H); 4.90 (t, 1H); 5.83 (d, 1H); 6.23 (d, 1H); 7.29 (d, 1H); 7.67 (d,1H)

Example 4

[0365](7E)-(1R,3R)-1,3-Dihydroxy-24a-(thiazol-2-yl-)-24-a-homo-19-nor-9,10-secochola-5,7-dien-24a-one29

[0366] 25. 100 mg of alcohol 26 is introduced into 6 ml ofdichloromethane, and 378 mg of manganese dioxide is added. It is stirredfor 2 hours at room temperature, then filtered on Celite, the solvent isremoved, and the residue is chromatographed on silica gel, whereby 78 mgof(7E)-(1R,3R)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one28 accumulates as a colorless foam.

[0367]¹H-NMR (CD₂Cl₂): δ=0.04 ppm (s, 12H); 0.51 (s, 3H); 0.84 (s, 18H);0.93 (d, 3H); 4.05 (m, 2H); 5.80 (d, 1H); 6.15 (d, 1H); 7.66 (d, 1H);7.97 (d, 1H)

[0368] 26. 78 mg of ketone 28 is introduced into 7 ml ofmethanol/dichloromethane (9:1), 780 mg of activated acid Dowex ionexchanger is added, and it is stirred for 1 day at room temperature. Itis filtered on Celite, rewashed thoroughly with dichloromethane, thesolvent is removed, and the residue is chromatographed on silica gel,whereby 43 mg of title compound 29 is obtained as a colorless foam.

[0369]¹H-NMR (CD₂Cl₂): δ=0.51 ppm (s, 3H); 0.97 (d, 3H); 3.97 (m, 1H);4.06 (m, 1H); 5.81 (d, 1H); 6.27 (d, 1H); 7.68 (d, 1H); 7.97 (d, 1H)

Example 5

[0370](5Z,7E)-(1S,3R,24aR)-24a-(Thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol32a and(5Z,7E)-(1S,3R,24aS)-24a-(thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol32b

[0371] 27. 309 mg of phosphine oxide 17, which was deprotonated with0.25 ml of n-butyllithium solution (2.5 M in hexane), is reacted with100 mg of ketone 24 analogously to 15., and 170 mg of(5Z,7E)-(1S,3R)-24a-(acetyloxy)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-(thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene30 is obtained as a colorless foam.

[0372]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.52 (s, 3H); 0.89 (s, 18H);0.90 (d, 3H); 2.18 (s, 3H); 4.19 (m, 1H); 4.38 (m, 1H); 4.87 (s, 1H);5.19 (s, 1H); 6.01 (d, 1H); 6.10 (t, 1H); 6.23 (d, 1H); 7.31 (d, 1H);7.83 (d, 1H)

[0373] 28. 170 mg of acetate 30 is reacted analogously to 13., and 149mg of(5Z,7E)-(1S,3R)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-(thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-ol31 is obtained as a colorless foam.

[0374]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.51 (s, 3H); 0.89 (s, 18H);0.90 (d, 3H); 2.18 (s, 3H); 4.18 (m, 1H); 4.38 (m, 1H); 4.87 (s, 1H);5.02 (m, 1H); 5.19 (s, 1H); 6.01 (d, 1H); 6.23 (d, 1H); 7.31 (d, 1H);7.74 (d, 1H)

[0375] 29. 101 mg of alcohol 31 is treated analogously to 14., and afterthe diastereomers (in terms of C-24a) are separated on HPLC, 24 mg oftitle compound 32a and 29 mg of title compound 32b are obtained ascolorless foams.

[0376]¹H-NMR (CD₂Cl₂/CD₃OD): 32a: δ=0.50 ppm (s, 3H); 0.90 (d, 3H); 4.11(m, 1H); 4.33 (m, 1H); 4.90 (t, 1H); 4.92 (s, 1H); 5.27 (s, 1H); 6.00(d, 1H); 6.32 (d, 1H); 7.29 (d, 1H); 7.68 (d, 1H)

[0377] 32b: δ=0.51 ppm (s, 3H); 0.89 (d, 3H); 4.11 (m, 1H); 4.33 (m,1H); 4.90 (t, 1H); 4.92 (s, 1H); 5.27 (s, 1H); 6.00 (d, 1H); 6.32 (d,1H); 7.29 (d, 1H); 7.68 (d, 1H)

Example 6

[0378](5Z,7E)-(1S,3R)-1,3-Dihydroxy-24a-(thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one34

[0379] 30. 149 mg of alcohol 31 is treated analogously to 25., and 127mg of(5Z,7E)-(1S,3R)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-(thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one33 is obtained as a colorless foam.

[0380]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.53 (s, 3H); 0.90 (s, 18H);0.97 (d, 3H); 4.19 (m, 1H); 4.38 (m, 1H); 4.88 (s, 1H); 5.19 (s, 1H);6.02 (d, 1H); 6.24 (d, 1H); 7.68 (d, 1H); 8.00 (d, 1H)

[0381] 31. 21 mg of ketone 33 is treated analogously to 26., and 8 mg oftitle compound 34 is obtained as a colorless foam.

[0382]¹H-NMR (CD₂Cl₂): δ=0.51 ppm (s, 3H); 0.94 (d, 3H); 4.17 (m, 1H);4.34 (m, 1H); 4.90 (s, 1H); 5.26 (s, 1H); 6.00 (d, 1H); 6.33 (d, 1H);7.66 (d, 1H); 7.97 (d, 1H)

Example 7

[0383](7E)-(1R,3R,24aR)-24a-(4-Methylthiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol41a and(7E)-(1R,3R,24aS)-24a-(4-methylthiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol41b

[0384] 32. 1.3 ml of 4-methylthiazole is introduced into 25 ml oftetrahydrofuran, and 5.78 ml of n-butyllithium solution (2.5 M inhexane) is added at −78° C. After 30 minutes at this temperature, 1.06 gof aldehyde 8 in 5 ml of tetrahydrofuran is added in drops, and it isstirred for 1 more hour. Then, it is quenched with sodium chloridesolution, extracted with ethyl acetate, the organic phase is washed withsodium chloride solution and dried on sodium sulfate. The solvent isremoved, and the residue is chromatographed on silica gel with ethylacetate/hexane, whereby 601 mg of[1R-[1α(1R*),3aβ,4α,7aα]]-α-[4-[octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1H-inden-1-yl]pentyl]-4-methylthiazol-2-methanol35 is obtained as a colorless oil.

[0385]¹H-NMR (CDCl₃): δ=0.56 ppm (q, 6H); 0.88 (d, 3H); 0.90 (s, 3H);0.97 (t, 9H); 2.41 (s, 3H); 4.02 (m, 1H); 4.94 (m, 1H); 6.82 (s, 1H)

[0386] 33. 601 mg of alcohol 35 is treated analogously to 9., and 589 mgof[1R-[1α(1R*),3aβ,4α,7aα]]-5-[octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1H-inden-1-yl]-1-(4-methylthiazol-2-yl)hexylacetate 36 is obtained as a colorless oil.

[0387]¹H-NMR (CDCl₃): δ=0.56 ppm (q, 6H); 0.85/0.86 (d, 3H); 0.91 (s,3H); 0.96 (t, 9H); 2.14 (s, 3H); 2.45 (s, 3H); 4.02 (m, 1H); 6.02 (t,1H); 6.81 (s, 1H)

[0388] 34. 589 mg of acetate 36 is treated analogously to 10., and 366mg of[1R-[1α(1R*),3aβ,4α,7aα]]-1-[5-(acetyloxy)-1-methyl-5-(4-methylthiazol-2-yl)pentyl]octahydro-7a-methyl-1H-inden-4-ol37 is obtained as a colorless oil.

[0389]¹H-NMR (CDCl₃): δ=0.87/0.88 ppm (d, 3H); 0.91 (s, 3H); 2.17 (s,3H); 2.45 (s, 3H); 4.07 (m, 1H); 6.03 (t, 1H); 6.81 (s, 1H)

[0390] 35. 360 mg of alcohol 37 is treated analogously to 11., and 340mg of[1R-[1α(1R*),3aβ,7aα]]-1-[5-(acetyloxy)-1-methyl-5-(2-methylthiazol-2-yl)pentyl]octahydro-7a-methyl-4H-inden-4-one38 is obtained as a colorless oil.

[0391]¹H-NMR (CDCl₃): δ=0.61 ppm (s, 3H); 0.92/0.93 (d, 3H); 2.13 (s,3H); 2.45 (s, 3H); 6.05 (t, 1H); 6.82 (s, 1H)

[0392] 36. 329 mg of phosphine oxide 13, which was deprotonated with0.28 ml of n-butyllithium solution (2.5 M in hexane), is reacted with113 mg of ketone 38 analogously to 12., and 98 mg of(7E)-(1R,3R)-24a-(acetyloxy)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-(4-methylthiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene39 is obtained as a colorless foam.

[0393]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.53 (s, 3H); 0.89 (s, 18H);0.90 (d, 3H); 2.15 (s, 3H); 2.46 (s, 3H); 4.09 (m, 2H); 5.81 (d, 1H);6.04 (t, 1H); 6.18 (d, 1H); 6.83 (s, 1H)

[0394] 37. 93 mg of acetate 39 is reacted analogously to 13., and 72 mgof(7E)-(1R,3R)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-(4-methylthiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-ol40 is obtained as a colorless foam.

[0395]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.53 (s, 3H); 0.89 (s, 18H);0.93 (d, 3H); 2.45 (s, 3H); 4.08 (m, 2H); 4.95 (m, 1H); 5.82 (d, 1H);6.18 (d, 1H); 6.82 (s, 1H)

[0396] 38. 72 mg of alcohol 40 is treated analogously to 14., and afterthe diastereomers (in terms of C-24a) are separated by HPLC, 15 mg oftitle compound 41a and 21 mg of title compound 41b are obtained ascolorless foams.

[0397]¹H-NMR (CD₂Cl₂): 41a: δ=0.51 ppm (s, 3H); 0.90 (d, 3H); 2.36 (s,3H); 3.94 (m, 1H); 4.02 (m, 1H); 4.88 (m, 1H); 5.83 (d, 1H); 6.24 (d,1H); 6.82 (s, 1H)

[0398] 41b: δ=0.51 ppm (s, 3H); 0.90 (d, 3H); 2.36 (s, 3H); 3.94 (m,1H); 4.02 (m, 1H); 4.86 (m, 1H); 5.83 (d, 1H); 6.24 (d, 1H); 6.83 (s,1H)

Example 8

[0399](7E)-(1R,3R)-1,3-Dihydroxy-24a-(4-methylthiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one43

[0400] 39. 53 mg of alcohol 40 is treated analogously to 25., whereby 42mg of(7E)-(1R,3R)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-(4-methylthiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one42 accumulates as a colorless foam.

[0401]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.53 (s, 3H); 0.89 (s, 18H);0.97 (d, 3H); 2.54 (s, 3H); 4.09 (m, 2H); 5.81 (d, 1H); 6.18 (d, 1H);7.23 (s, 1H)

[0402] 40. 42 mg of ketone 42 is treated analogously to 26., whereby 13mg of title compound 43 accumulates as a colorless foam.

[0403]¹H-NMR (CD₂Cl₂/CD₃OD): δ=0.52 ppm (s, 3H); 0.93 (d, 3H); 2.48 (s,3H); 3.94 (m, 1H); 4.03 (m, 1H); 5.82 (d, 1H); 6.23 (d, 1H); 7.23 (s,1H)

Example 9

[0404](5Z,7E)-(1S,3R,24aR)-24a-(4-Methylthiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol46a and(5Z,7E)-(1S,3R,24aS)-24a-(4-methylthiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol46b

[0405] 41. 337 mg of phosphine oxide 17, which was deprotonated with0.28 ml of n-butyllithium solution (2.5 M in hexane), is reacted with113 mg of ketone 38 analogously to 15., and 170 mg of(5Z,7E)-(1S,3R)-24a-(acetyloxy)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-(4-methylthiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene44 is obtained as a colorless foam.

[0406]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.52 (s, 3H); 0.89 (s, 18H);0.90 (d, 3H); 2.14 (s, 3H); 2.45 (s, 3H); 4.19 (m, 1H); 4.38 (m, 1H);4.88 (s, 1H); 5.19 (s, 1H); 6.02 (d, 1H); 6.03 (m, 1H); 6.23 (d, 1H);6.83 (s, 1H)

[0407] 42. 170 mg of acetate 44 is reacted analogously to 13., and 109mg of(5Z,7E)-(1S,3R)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-(4-methylthiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-ol45 is obtained as a colorless foam.

[0408]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.52 (s, 3H); 0.90 (s, 18H);0.93 (d, 3H); 2.45 (s, 3H); 4.19 (m, 1H); 4.38 (m, 1H); 4.88 (s, 1H);4.95 (m, 1H); 5.19 (s, 1H); 6.02 (d, 1H); 6.23 (d, 1H); 6.83 (s, 1H)

[0409] 43. 105 mg of alcohol 45 is treated analogously to 14., and afterthe diastereomers (in terms of C-24a) are separated by HPLC, 30 mg oftitle compound 46a and 29 mg of title compound 46b are obtained ascolorless foams.

[0410]¹H-NMR (CD₂Cl₂): δ=0.50 ppm (s, 3H); 0.90 (d, 3H); 2.38 (s, 3H);4.17 (m, 1H); 4.36 (m, 1H); 4.88 (dd, 1H); 4.94 (s, 1H); 5.27 (s, 1H);6.00 (d, 1H); 6.36 (d, 1H); 6.81 (s, 1H)

[0411] 46b: δ=0.50 ppm (s, 3H); 0.89 (d, 3H); 2.38 (s, 3H); 4.17 (m,1H); 4.36 (m, 1H); 4.84 (dd, 1H); 4.94 (s, 1H); 5.27 (s, 1H); 6.00 (d,1H); 6.35 (d, 1H); 6.81 (s, 1H)

Example 10

[0412](5Z,7E)-(1S,3R)-1,3-Dihydroxy-24a-(4-methylthiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one48

[0413] 44. 48 mg of alcohol 45 is treated analogously to 25., and 40 mgof(5Z,7E)-(1S,3R)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]-oxy]-24a-(4-methylthiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one47 is obtained as a colorless foam.

[0414]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.52 (s, 3H); 0.88 (s, 18H);0.95 (d, 3H); 2.52 (s, 3H); 4.19 (m, 1H); 4.37 (m, 1H); 4.84 (s, 1H);5.18 (s, 1H); 6.00 (d, 1H); 6.23 (d, 1H); 7.21 (s, 1H)

[0415] 45. 39 mg of ketone 47 is treated analogously to 26., and 11 mgof title compound 48 is obtained as a colorless foam.

[0416]¹H-NMR (CD₂Cl₂): δ=0.53 ppm (s, 3H); 0.95 (d, 3H); 2.45 (s, 3H);4.15 (m, 1H); 4.36 (m, 1H); 4.95 (s, 1H); 5.27 (s, 1H); 6.00 (d, 1H);6.35 (d, 1H); 7.24 (s, 1H)

Example 11

[0417](7E)-(1R,3R,24aR)-24a-(Thien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol55a and(7E)-(1R,3R,24aS)-24a-(thien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol55b

[0418] 46. 0.65 ml of thiophene is introduced into 20 ml oftetrahydrofuran, and 3.27 ml of n-butyllithium solution (2.5 M inhexane) is added at −78° C. After 30 minutes at this temperature, 600 mgof aldehyde 8 in 3 ml of tetrahydrofuran is added in drops, and it isstirred for 1 more hour. Then, it is quenched with sodium chloridesolution, extracted with ethyl acetate, the organic phase is washed withsodium chloride solution and dried on sodium sulfate. The solvent isremoved, and the residue is chromatographed on silica gel with ethylacetate/hexane, whereby 673 mg of[1R-[1α(1R*),3aβ,4α,7aα]]-α-[4-[octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1H-inden-1-yl]pentyl]thiophene-2-methanol49 is obtained as a colorless oil.

[0419]¹H-NMR (CDCl₃): δ=0.56 ppm (q, 6H); 0.89 (d, 3H); 0.91 (s, 3H);0.97 (t, 9H); 4.03 (m, 1H); 4.93 (m, 1H); 6.98 (m, 2H); 7.27 (m, 1H)

[0420] 47. 673 mg of alcohol 49 is treated analogously to 9., and 712 mgof[1R-[1α(1R*),3aβ,4α,7aα]]-5-[octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1H-inden-1-yl]-1-(thien-2-yl)hexyl-acetate50 is obtained as a colorless oil.

[0421]¹H-NMR (CDCl₃): δ=0.56 ppm (q, 6H); 0.87/0.88 (d, 3H); 0.91 (s,3H); 0.97 (t, 9H); 2.08 (s, 3H); 4.02 (m, 1H); 6.05 (t, 1H); 6.98 (m,1H); 7.05 (m, 1H); 7.27 (m, 1H)

[0422] 48. 704 mg of acetate 50 is treated analogously to 10., and 412mg of[1R-[1α(1R*),3aβ,4α,7aα]]-1-[5-(acetyloxy)-1-methyl-5-(thien-2-yl)pentyl]octahydro-7a-methyl-1H-inden-4-ol51 is obtained as a colorless oil.

[0423]¹H-NMR (CDCl₃): δ=0.87/0.88 ppm (d, 3H); 0.92 (s, 3H); 2.08 (s,3H); 4.07 (m, 1H); 6.03 (t, 1H); 6.97 (m, 1H); 7.07 (m, 1H); 7.28 (m,1H)

[0424] 49. 407 mg of alcohol 51 is treated analogously to 11., and 373mg of[1R-[1α(1R*),3aβ,7aα]]-1-[5-(acetyloxy)-1-methyl-5-(thien-2-yl)pentyl]octahydro-7a-methyl-4H-inden-4-one52 is obtained as a colorless oil.

[0425]¹H-NMR (CDCl₃): δ=0.62 ppm (s, 3H); 0.92/0.93 (d, 3H); 2.08 (s,3H); 6.04 (t, 1H); 6.98 (m, 1H); 7.05 (m, 1H); 7.28 (m, 1H)

[0426] 50. 329 mg of phosphine oxide 13, which was deprotonated with0.28 ml of n-butyllithium solution (2.5 M in hexane), is reacted with109 mg of ketone 52 analogously to 12., and 183 mg of(7E)-(1R,3R)-24a-(acetyloxy)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-(thien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene53 is obtained as a colorless foam.

[0427]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.53 (s, 3H); 0.90 (s, 18H);0.90 (d, 3H); 2.07 (s, 3H); 4.08 (m, 2H); 5.81 (d, 1H); 6.04 (t, 1H);6.18 (d, 1H); 6.98 (m, 1H); 7.05 (m, 1H); 7.29 (m, 1H)

[0428] 51. 178 mg of acetate 53 is reacted analogously to 13., and 138mg of(7E)-(1R,3R)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]-oxy]-24a-(thien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-ol54 is obtained as a colorless foam.

[0429]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.53 (s, 3H); 0.89 (s, 18H);0.91 (d, 3H); 4.09 (m, 2H);-4.94 (m, 1H); 5.82 (d, 1H); 6.18 (d, 1H);6.98 (m, 2H); 7.28 (m, 1H)

[0430] 52. 97 mg of alcohol 54 is treated analogously to 14., and afterthe diastereomers (in terms of C-24a) are separated by HPLC, 19 mg oftitle compound 55a and 24 mg of title compound 55b are obtained ascolorless foams.

[0431]¹H-NMR (CD₂Cl₂): 55a: δ=0.52 ppm (s, 3H); 0.90 (d, 3H); 3.95 (m,1H); 4.02 (m, 1H); 4.87 (dd, 1H); 5.84 (d, 1H); 6.25 (d, 1H); 6.98 (m,2H); 7.23 (m, 1H)

[0432] 41b: δ=0.52 ppm (s, 3H); 0.89 (d, 3H); 3.95 (m, 1H); 4.02 (m,1H); 4.86 (t, 1H); 5.84 (d, 1H); 6.25 (d, 1H); 6.97 (m, 2H); 7.22 (m,1H)

Example 12

[0433](7E)-(1R,3R)-1,3-Dihydroxy-24a-(thien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one57

[0434] 53. 40 mg of alcohol 54 is treated analogously to 25., whereby 28mg of(7E)-(1R,3R)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]-oxy]-24a-(thien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one56 accumulates as a colorless foam.

[0435]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.53 (s, 3H); 0.88 (s, 18H);0.98 (d, 3H); 4.09 (m, 2H); 5.81 (d, 1H); 6.18 (d, 1H); 7.14 (dd, 1H);7.62 (d, 1H); 7.72 (d, 1H)

[0436] 54. 27 mg of ketone 42 is treated analogously to 26., whereby 13mg of title compound 57 accumulates as a colorless foam.

[0437]¹H-NMR (CD₂Cl₂): δ=0.52 ppm (s, 3H); 0.92 (d, 3H); 3.93 (m, 1H);4.03 (m, 1H); 5.82 (d, 1H); 6.23 (d, 1H); 7.12 (dd, 1H); 7.60 (d, 1H);7.67 (d, 1H)

Example 13

[0438](5Z,7E)-(1S,3R,24aR)-24a-(Thien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol60a and(5Z,7E)-(1S,3R,24aS)-24a-(thien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol60b

[0439] 55. 350 mg of phosphine oxide 17, which was deprotonated with0.29 ml of n-butyllithium solution (2.5 M in hexane), is reacted with113 mg of ketone 52 analogously to 15, and 93 mg of(5Z,7E)-(1S,3R)-24a-(acetyloxy)-1,3-bis-[((1,1-dimethylethyl)dimethylsilyl]oxy]-24a-(thien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene58 is obtained as a colorless foam.

[0440]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.53 (s, 3H); 0.90 (s, 18H);0.90 (d, 3H); 2.07 (s, 3H); 4.19 (m, 1H); 4.38 (m, 1H); 4.88 (s, 1H);5.20 (s, 1H); 6.01 (d, 1H); 6.02 (t, 1H); 6.24 (d, 1H); 6.98 (m, 1H);7.06 (m, 1H); 7.28 (m, 1H)

[0441] 56. 92 mg of acetate 58 is reacted analogously to 13., and 79 mgof(5Z,7E)-(1S,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]-oxy]-24a-(thien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-ol59 is obtained as a colorless foam.

[0442]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.52 (s, 3H); 0.88 (s, 18H);0.90 (d, 3H); 4.18 (m, 1H); 4.38 (m, 1H); 4.88 (s, 1H); 4.93 (m, 1H);5.18 (s, 1H); 6.00 (d, 1H); 6.22 (d, 1H); 6.98 (m, 2H); 7.28 (m, 1H)

[0443] 57. 78 mg of alcohol 59 is treated analogously to 14., and afterthe diastereomers (in terms of C-24a) are separated by HPLC, 21 mg oftitle compound 60a and 24 mg of title compound 60b are obtained ascolorless foams.

[0444]¹H-NMR (CD₂Cl₂/CD₃OD): 60a: δ=0.50 ppm (s, 3H); 0.88 (d, 3H); 4.10(m, 1H); 4.32 (m, 1H); 4.86 (dd, 1H); 494 (s, 1H); 5.26 (s, 1H); 6.00(d, 1H); 6.27 (d, 1H); 6.92 (m, 2H); 7.20 (m, 1H)

[0445] 60b: δ=0.50 ppm (s, 3H); 0.86 (d, 3H); 4.10 (m, 1H); 4.31 (m,1H); 4.83 (t, 1H); 4.94 (s, 1H); 5.26 (s, 1H); 6.00 (d, 1H); 6.27 (d,1H); 6.92 (m, 2H); 7.20 (m, 1H)

Example 14

[0446](7E)-(1R,2S,3R,24aR)-24a-Thien-2-yl-24a-homo-19-nor-9,10-secochola-5,7-diene-1,2,3,24-tetrol64a and(7E)-(1R,2S,3R,24aS)-24a-thien-2-yl-24a-homo-19-nor-9,10-secochola-5,7-diene-1,2,3,24-tetrol64b

[0447] 58. 405 mg of[2-[[3R-(3R,4S,5R)]-3,4,5-tris[[(1,1-dimethylethyl)dimethylsilyl]oxy]cyclo-hexylidene]ethyl]diphenylphosphineoxide 61a [H. F. DeLuca et al. J. Med. Chem. 37, 3730 (1994)] isintroduced into 6 ml of tetrahydrofuran, and 0.28 ml of n-butyllithiumsolution (2.5 M in hexane) is added in drops at −78° C. At −30° C., 109mg of ketone 52 is added after 10 minutes, and it is stirred for 1 hourat this temperature. Then, it is quenched with sodium chloride solution,extracted with ethyl acetate, the organic phase is washed with sodiumchloride solution, dried on sodium sulfate, and the solvent is removed.The residue is chromatographed on silica gel with ethyl acetate/hexane,whereby 206 mg of(7E)-(1R,2S,3R)-24a-(acetyloxy)-24a-(thien-2-yl)-1,2,3-tris[[(1,1-dimethylethyl)dimethylsilyl]-oxy]-24a-homo-19-nor-9,10-secochola-5,7-diene62 is obtained as a colorless foam.

[0448]¹H-NMR (CDCl₃): δ=0.02-0.07 ppm (4×s, 18H); 0.53 (s, 3H); 0.83 (s,9H); 0.89 (s, 18H); 0.90 (d, 3H); 2.07 (s, 3H); 3.64 (m, 1H); 3.80 (m,1H); 3.85 (m, 1H); 5.84 (d, 1H); 6.03 (t, 1H); 6.04 (d, 1H); 6.97 (m,2H); 7.05 (m, 1H)

[0449] 59. 205 mg of acetate 62 is reacted analogously to 13., and 180mg of(7E)-(1R,2S,3R)-24a-(thien-2-yl)-1,2,3-tris[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-ol63 is obtained as a colorless foam.

[0450]¹H-NMR (CDCl₃): δ=0.02-0.07 ppm (4×s, 18H); 0.53 (s, 3H); 0.83 (s,9H); 0.89 (s, 18H); 0.90 (d, 3H); 3.63 (m, 1H); 3.79 (m, 1H); 3.83 (m,1H); 4.93 (m, 1H); 5.83 (d, 1H); 6.04 (d, 1H); 6.99 (m, 2H); 7.28 (m,1H)

[0451] 60. 134 mg of alcohol 63 is treated analogously to 14., and afterthe diastereomers (in terms of C-24a) are separated by HPLC, 18 mg oftitle compound 64a and 25 mg of title compound 64b are obtained ascolorless foams.

[0452]¹H-NMR (CD₂Cl₂): 64a: δ=0.52 ppm (s, 3H); 0.89 (d, 3H); 3.44 (dd,1H); 3.72 (m, 1H); 4.00 (m, 1H); 4.87 (dd, 1H); 5.76 (d, 1H); 6.28 (d,1H); 6.93 (m, 2H); 7.22 (m, 1H)

[0453] 64b: δ=0.53 ppm (s, 3H); 0.90 (d, 3H); 3.46 (dd, 1H); 3.70 (m,1H); 4.00 (m, 1H); 4.87 (t, 1H); 5.77 (d, 1H); 6.28 (d, 1H); 6.93 (m,2H); 7.21 (m, 1H)

Example 15

[0454](7E)-(1R,2S,3R)-24a-Thien-2-yl-1,2,3-trihydroxy-24a-homo-9,10-secochola-5,7-dien-24a-one66

[0455] 61. 45 mg of alcohol 63 is treated analogously to 25., whereby 38mg of(7E)-(1R,2S,3R)-24a-(thien-2-yl)-1,2,3-tris[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one65 accumulates as a colorless foam.

[0456]¹H-NMR (CDCl₃): δ=0.02-0.07 ppm (4×s, 18H); 0.53 (s, 3H); 0.83 (s,9H); 0.90 (s, 18H); 0.97 (d, 3H); 3.62 (m, 1H); 3.80 (m, 1H); 3.85 (m,1H); 5.85 (d, 1H) 6.06 (d, 1H); 7.12 (dd, 1H); 7.61 (d, 1H); 7.70 (d,1H)

[0457] 62. 38 mg of ketone 65 is treated analogously to 26., whereby 13mg of title compound 66 accumulates as a colorless foam.

[0458]¹H-NMR (CD₂Cl₂): δ=0.53 ppm (s, 3H); 0.95 (d, 3H); 3.48 (m, 1H);3.74 (m, 1H); 4.03 (m, 1H); 5.85 (d, 1H); 6.30 (d, 1H); 7.13 (dd, 1H);7.61 (d, 1H); 7.69 (d, 1H)

Example 16

[0459](7E)-(1R,3R,24aR)-24a-(4-Methylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol73a and(7E)-(1R,3R,24aS)-24a-(4-methylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol73b

[0460] 63. 0.79 ml of 3-methylthiophene is introduced into 20 ml oftetrahydrofuran, and 3.27 ml of n-butyllithium solution (2.5 M inhexane) is aded at −78° C. After 30 minutes at this temperature, 600 mgof aldehyde 8 in 3 ml of tetrahydrofuran is added in drops, and it isstirred for 1 more hour. Then, it is quenched with sodium chloridesolution, extracted with ethyl acetate, the organic phase is washed withsodium chloride solution and dried on sodium sulfate. The solvent isremoved, and the residue is chromatographed on silica gel with ethylacetate/hexane, whereby 681 mg of[1R-[1α(1R*),3aβ,4α,7aα]]-α-[4-(octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1H-inden-1-yl]pentyl]-4-methylthiophene-2-methanol67 is obtained as a colorless oil.

[0461]¹H-NMR (CDCl₃): δ=0.55 ppm (q, 6H); 0.88 (d, 3H); 0.90 (s, 3H);0.96 (t, 9H); 2.23 (s, 3H); 4.03 (m, 1H); 4.83 (m, 1H) 6.80 (s, 1H);6.82 (s, 1H)

[0462] 64. 671 mg of alcohol 67 is treated analogously to 9., and 692 mgof[1R-[1α(R*),3aβ,4α,7aα]]-5-[octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1H-inden-1-yl]-1-(4-methylthien-2-yl)hexyl-acetate68 is obtained as a colorless oil.

[0463]¹H-NMR (CDCl₃): δ=0.56 ppm (q, 6H); 0.87/0.88 (d, 3H); 0.90 (s,3H); 0.96 (t, 9H); 2.08 (s, 3H); 2.25 (s, 3H); 4.03 (m, 1H); 5.98 (t,1H); 6.83 (s, 1H); 6.85 (s, 1H)

[0464] 65. 682 mg of acetate 68 is treated analogously to 10., and 425mg of[1R-[1α(1R*),3aβ,4α,7aα]]-1-[5-(acetyloxy)-1-methyl-5-(4-methylthien-2-yl)pentyl]octahydro-7a-methyl-1H-inden-4-ol69 is obtained as a colorless oil.

[0465]¹H-NMR (CDCl₃): δ=0.87/0.88 ppm (d, 3H); 0.92 (s, 3H); 2.08 (s,3H); 2.23 (s, 3H); 4.07 (m, 1H); 5.98 (t, 1H); 6.82 (s, 1H); 6.85 (s,1H)

[0466] 66. 415 mg of alcohol 69 is treated analogously to 11., and 352mg of[1R-[1α(1R*),3aβ,7aα]]-1-[5-(acetyloxy)-1-methyl-5-(4-methylthien-2-yl)pentyl]octahydro-7a-methyl-4H-inden-4-one70 is obtained as a colorless oil.

[0467]¹H-NMR (CDCl₃): δ=0.62 ppm (s, 3H); 0.92/0.93 (d, 3H); 2.08 (s,3H); 2.25 (s, 3H); 5.97 (t, 1H); 6.83 (s, 1H); 6.84 (s, 1H)

[0468] 67. 306 mg of phosphine oxide 13, which was deprotonated with0.26 ml of n-butyllithium solution, is reacted with 105 mg of ketone(7E)-(1R,3R)-24a-(acetyloxy)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-(4-methylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene70 analogously to 12., and 166 mg of 71 is obtained as a colorless foam.

[0469]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.53 (s, 3H); 0.90 (s, 18H);0.91 (d, 3H); 2.07 (s, 3H); 2.23 (s, 3H); 4.09 (m, 2H); 5.81 (d, 1H);5.97 (t, 1H); 6.18 (d, 1H); 6.82 (s, 1H); 6.84 (s, 1H)

[0470] 68. 165 mg of acetate 71 is treated analogously to 13., and 128mg of(7E)-(1R,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-24a-(4-methylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-ol72 is obtained as a colorless foam.

[0471]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.54 (s, 3H); 0.89 (s, 18H);0.91 (d, 3H); 2.25 (s, 3H); 4.09 (m, 2H); 4.85 (m, 1H); 5.82 (d, 1H);6.18 (d, 1H); 6.80 (s, 1H); 6.82 (s, 1H)

[0472] 69. 91 mg of alcohol 72 is treated analogously to 14., and afterthe diastereomers (in terms of C-24a) are separated by HPLC, 16 mg oftitle compound 73a and 19 mg of title compound 73b are obtained ascolorless foams.

[0473]¹H-NMR (CD₂Cl₂/CD₃OD): 73a: δ=0.51 ppm (s, 3H); 0.91 (d, 3H); 2.18(s, 3H); 3.94 (m, 1H); 4.02 (m, 1H); 4.76 (t, 1H); 5.84 (d, 1H); 6.25(d, 1H); 6.75 (s, 1H); 6.77 (s, 1H);

[0474] 73b: δ=0.51 ppm (s, 3H); 0.90 (d, 3H); 2.18 (s, 3H); 3.94 (m,1H); 4.02 (m, 1H); 4.78 (t, 1H); 5.84 (d, 1H); 6.25 (d, 1H); 6.75 (s,1H); 6.77 (s, 1H)

Example 17

[0475](7E)-(1R,3R)-1,3-Dihydroxy-24a-(4-methylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one75

[0476] 70. 36 mg of alcohol 72 is treated analogously to 25., whereby 30mg of(7E)-(1R,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-24a-(4-methylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one74 accumulates as a colorless foam.

[0477]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.54 (s, 3H); 0.88 (s, 18H);0.98 (d, 3H); 2.30 (s, 3H); 4.09 (m, 2H); 5.82 (d, 1H); 6.18 (d, 1H);7.22 (s, 1H); 7.52 (s, 1H)

[0478] 71. 29 mg of ketone 74 is treated analogously to 26., whereby 13mg of 75 of the title compound accumulates as a colorless foam.

[0479]¹H-NMR (CD₂Cl₂): δ=0.52 ppm (s, 3H); 0.94 (d, 3H); 2.27 (s, 3H);3.95 (m, 1H); 4.04 (m, 1H); 5.82 (d, 1H); 6.24 (d, 1H); 7.19 (s, 1H);7.48 (s, 1H)

Example 18

[0480](5Z,7E)-(1S,3R,24aR)-24a-(4-Methylthien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol78a and(5Z,7E)-(1S,3R,24aS)-24a-(4-methylthien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol78b

[0481] 72. 316 mg of phosphine oxide 17, which was deprotonated with0.26 ml of n-butyllithium solution (2.5 M in hexane), is reacted with106 mg of ketone 70 analogously to 15., and 177 mg of(5Z,7E)-(1S,3R)-24a-(acetyloxy)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-(4-methylthien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene76 is obtained as a colorless foam.

[0482]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.53 (s, 3H); 0.89 (s, 18H);0.90 (d, 3H); 2.08 (s, 3H); 2.23 (s, 3H); 4.19 (m, 1H); 4.38 (m, 1H);4.88 (s, 1H); 5.20 (s, 1H); 5.98 (t, 1H); 6.01 (d, 1H); 6.23 (d, 1H);6.83 (s, 1H); 6.85 (s, 1H)

[0483] 73. 176 mg of acetate 76 is reacted analogously to 13., and 149mg of(5Z,7E)-(1S,3R)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]-oxy]-24a-(4-methylthien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-ol77 is obtained as a colorless foam.

[0484]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.53 (s, 3H); 0.89 (s, 18H);0.90 (d, 3H); 2.23 (s, 3H); 4.19 (m, 1H); 4.38 (m, 1H); 4.88 (s, 1H);4.95 (m, 1H); 5.19 (s, 1H); 6.02 (d, 1H); 6.25 (d, 1H); 6.80 (s, 1H);6.82 (s, 1H)

[0485] 74. 103 mg of alcohol 77 is treated analogously to 14., and afterthe diastereomers (in terms of C-24a) are separated by HPLC, 26 mg oftitle compound 78a and 27 mg of title compound 78b are obtained ascolorless foams.

[0486]¹H-NMR (CD₂Cl₂/CD₃OD): 78a: δ=0.50 ppm (s, 3H); 0.88 (d, 3H); 2.17(s, 3H); 4.09 (m, 1H); 4.30 (m, 1H); 4.76 (t, 1H); 4.92 (s, 1H); 5.27(s, 1H); 6.00 (d, 1H); 6.28 (d, 1H); 6.82 (s, 1H); 6.84 (s, 1H)

[0487] 78b: δ=0.50 ppm (s, 3H); 0.89 (d, 3H); 2.17 (s, 3H); 4.09 (m,1H): 4.30 (m, 1H); 4.78 (t, 1H); 4.92 (s, 1H); 5.27 (s, 1H); 6.00 (d,1H); 6.28 (d, 1H); 6.82 (s, 1H); 6.84 (s, 1H)

Example 19

[0488](5Z,7E)-(1S,3R)-1,3-Dihydroxy-24a-(4-methylthien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one80

[0489] 75. 45 mg of alcohol 77 is treated analogously to 25., whereby 20mg of(5Z,7E)-(1S,3R)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-(4-methylthien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one79 accumulates as-a colorless foam.

[0490]¹H-NMR (CDCl₃): δ=0.06 ppm (s, 12H); 0.53 (s, 3H); 0.88 (s, 18H);0.97 (d, 3H); 2.29 (s, 3H); 4.18 (m, 1H); 4.38 (m, 1H); 4.96 (s, 1H);5.18 (s, 1H); 6.00 (d, 1H); 6.23 (d, 1H); 7.22 (s, 1H); 7.52 (s, 1H)

[0491] 76. 19 mg of ketone 79 is treated analogously to 26., whereby 9mg of title compound 80 accumulates as a colorless foam.

[0492]¹H-NMR (CD₂Cl₂): δ=0.52 ppm (s, 3H); 0.94 (d, 3H); 2.27 (s, 3H);4.16 (m, 1H); 4.36 (m, 1H); 4.94 (s, 1H); 5.28 (s, 1H); 5.98 (d, 1H);6.36 (d, 1H); 7.20 (s, 1H); 7.48 (s, 1H)

Example 20

[0493](7E)-(1R,2S,3R,24aR)-24a-(4-Methylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,2,3,24-tetrol83a and(7E)-(1R,2S,3R,24aS)-24a-(4-methylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,2,3,24-tetrol83b

[0494] 77. 377 mg of phosphine oxide 61a is introduced into 6 ml oftetrahydrofuran, and 0.26 ml of n-butyllithium solution (2.5 M inhexane) is added in drops at −78° C. 105 mg of ketone 70 is added at−30° C. after 10 minutes, and it is stirred for 1 hour at thistemperature. Then, it is quenched with sodium chloride solution,extracted with ethyl acetate, the organic phase is washed with sodiumchloride solution, dried on sodium sulfate, and the solvent is removed.The residue is chromatographed on silica gel with ethyl acetate/hexane,whereby 174 mg of(7E)-(1R,2S,3R)-24a-(acetyloxy)-24a-(4-methylthien-2-yl)-1,2,3-tris[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-homo-19-nor-9,10-secochola-5,7-diene81 is obtained as a colorless foam.

[0495]¹H-NMR (CDCl₃): δ=0.02-0.07 ppm (4×s, 18H); 0.53 (s, 3H); 0.83 (s,9H); 0.89 (s, 18H); 0.90 (d, 3H); 2.06 (s, 3H); 2.22 (s, 3H); 3.63 (m,1H); 3.80 (m, 1H); 3.85 (m, 1H); 5.85 (d, 1H); 5.97 (t, 1H); 6.05 (d,1H); 6.82 (s, 2H); 6.84 (s, 1H)

[0496] 78. 173 mg of acetate 81 is reacted analogously to 13., and 146mg of(7E)-(1R,2S,3R)-24a-(4-methylthien-2-yl)-1,2,3-tris[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-ol82 is obtained as a colorless foam.

[0497]¹H-NMR (CDCl₃): δ=0.02-0.07 ppm (4×s, 18H); 0.53 (s, 3H); 0.83 (s,9H); 0.89 (s, 18H); 0.90 (d, 3H); 2.22 (s, 3H); 3.63 (m, 1H); 3.79 (m,1H); 3.84 (m, 1H); 4.93 (m, 1H); 5.83 (d, 1H); 6.04 (d, 1H); 6.78 (s,1H); 6.80 (s, 1H)

[0498] 79. 99 mg of alcohol 82 is treated analogously to 14., and afterthe diastereomers (in terms of C-24a) are separated by HPLC, 19 mg oftitle compound 83a and 23 mg of title compound 83b are obtained ascolorless foams.

[0499]¹H-NMR (CD₂Cl₂): 83a: δ=0.52 ppm (s, 3H); 0.88 (d, 3H); 2.18 (s,3H); 3.45 (m, 1H); 3.70 (m, 1H); 4.00 (m, 1H); 4.78 (t, 1H); 5.77 (d,1H); 6.28 (d, 1H); 6.86 (s, 1H); 6.88 (s, 1H)

[0500] 83b: δ=0.52 ppm (s, 3H); 0.89 (d, 3H); 2.18 (s, 3H); 3.45 (m,1H); 3.70 (m, 1H); 4.00 (m, 1H); 4.80 (t, 1H); 5.77 (d, 1H); 6.28 (d,1H); 6.86 (s, 1H); 6.89 (s, 1H)

Example 21

[0501](7E)-(1R,2S,3R)-24a-(4-Methylthien-2-yl)-1,2,3-trihydroxy-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one85

[0502] 80. 46 mg of alcohol 82 is treated analogously to 25., whereby 41mg of(7E)-(1R,2S,3R)-24a-(4-methylthien-2-yl)-1,2,3-tris[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one84 accumulates as a colorless foam.

[0503]¹H-NMR (CDCl₃): δ=0.02-0.07 ppm (4×s, 18H); 0.53 (s, 3H); 0.83 (s,9H); 0.89 (s, 18H); 0.97 (d, 3H); 2.28 (s, 3H); 3.63 (m, 1H); 3.79 (m,1H); 3.84 (m, 1H); 5.83 (d, 1H); 6.05 (d, 1H); 7.21 (s, 1H); 7.51 (s,1H)

[0504] 81. 40 mg of ketone 84 is treated analogously to 26., whereby 18mg of title compound 85 accumulates as a colorless foam.

[0505]¹H-NMR (CD₂Cl₂): δ=0.53 ppm (s, 3H); 0.95 (d, 3H); 2.26 (s, 3H);3.47 (m, 1H); 3.70 (m, 1H); 4.01 (m, 1H); 5.77 (d, 1H); 6.30 (d, 1H);7.20 (s, 1H); 7.50 (s, 1H)

Example 22

[0506](7E)-(1R,3R,24aR)-24a-(5-Ethylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol92a and(7E)-(1R,3R,24aS)-24a-(5-ethylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol92b

[0507] 82. 1.19 ml of 2-ethylthiophene is introduced into 20 ml oftetrahydrofuran, and 4.2 ml of n-butyllithium solution (2.5 M in hexane)is added at −78° C. After 30 minutes at this temperature, 770 mg ofaldehyde 8 in 5 ml of tetrahydrofuran is added in drops, and it isstirred for 1 more hour. Then, it is quenched with sodium chloridesolution, extracted with ethyl acetate, the organic phase is washed withsodium chloride solution and dried on sodium sulfate. The solvent isremoved, and the residue is chromatographed on silica gel with ethylacetate/hexane, whereby 773 mg of[1R-[1α(1R*),3aβ,4α,7aα]]-5-ethyl-α-[4-[octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1H-inden-1-yl]pentyl]thiophene-2-methanol86 is obtained as a colorless oil.

[0508]¹H-NMR (CDCl₃): δ=0.56 ppm (q, 6H); 0.89 (d, 3H); 0.90 (s, 3H);0.97 (t, 9H); 1.31 (t, 3H); 2.82 (q, 2H); 4.03 (m, 1H); 4.81 (m, 1H);6.62 (d, 1H); 6.80 (d, 1H)

[0509] 83. 763 mg of alcohol 86 is treated analogously to 9., and 745 mgof[1R-[1α(1R*),3aβ,4α,7aα]]-1-(5-ethylthien-2-yl)-5-[octahydro-7a-methyl-4-[(triethyl-silyl]oxy]-1H-inden-1-yl]hexyl-acetate87 is obtained as a colorless oil.

[0510]¹H-NMR (CDCl₃): δ=0.55 ppm (q, 6H); 0.8710.88 (d, 3H); 0.90 (s,3H); 0.95 (t, 9H); 1.30 (t, 3H); 2.07 (s, 3H); 2.82 (q, 2H); 4.03 (m,1H); 5.97 (t, 1H); 6.62 (d, 1H); 6.87 (d, 1H)

[0511] 84. 682 mg of acetate 87 is treated analogously to 10., and 287mg of[1R-[1α(1R*),3aβ,4α,7aα]]-1-[5-(acetyloxy)-5-(5-ethylthien-2-yl)-1-methylpentyl]octahydro-7a-methyl-1H-inden-4-ol88 is obtained as a colorless oil.

[0512]¹H-NMR (CDCl₃): δ=0.87/0.88 ppm (d, 3H); 0.92 (s, 3H); 1.31 (t,3H); 2.08 (s, 3H); 2.82 (q, 2H); 4.07 (m, 1H); 5.97 (t, 1H); 6.63 (d,1H); 6.85 (d, 1H)

[0513] 85. 142 mg of alcohol 88 is treated analogously to 11., and 123mg of[1R-[1α(1R*),3aβ,7aα]]-1-[5-(acetyloxy)-5-(5-ethylthien-2-yl)-1-methylpentyl]octahydro-7a-methyl-4H-inden-4-one89 is obtained as a colorless oil.

[0514]¹H-NMR (CDCl₃): δ=0.62 ppm (s, 3H); 0.92/0.93 (d, 3H); 1.30 (t,3H); 2.07 (s, 3H); 2.82 (q, 2H); 5.97 (t, 1H); 6.62 (d, 1H); 6.86 (d,1H)

[0515] 86. 347 mg of phosphine oxide 13, which was deprotonated with 0.3ml of n-butyllithium solution (2.5 M in hexane), is reacted with 123 mgof ketone 89 analogously to 12., and 129 mg of(7E)-(1R,3R)-24a-(acetyloxy)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-(5-ethylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene90 is obtained as a colorless foam.

[0516]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.53 (s, 3H); 0.90 (s, 18H);0.91 (d, 3H); 1.30 (t, 3H); 2.07 (s, 3H); 2.82 (q, 2H); 4.09 (m, 2H);5.82 (d, 1H); 5.96 (t, 1H); 6.18 (d, 1H); 6.62 (d, 1H); 6.86 (d, 1H).

[0517] 87. 129 mg of acetate 90 is reacted analogously to 13., and 98 mgof(7E)-(1R,3R)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]-oxy]-24a-(5-ethylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-ol91 is obtained as a colorless foam.

[0518]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.54 (s, 3H); 0.89 (s, 18H);0.91 (d, 3H); 1.30 (t, 3H); 2.82 (q, 2H); 4.10 (m, 2H); 4.84 (m, 1H);5.82 (d, 1H); 6.18 (d, 1H); 6.63 (d, 1H); 6.80 (d, 1H)

[0519] 88. 98 mg of alcohol 91 is treated analogously to 14., and afterthe diastereomers (in terms of C-24a) are separated by HPLC, 18 mg oftitle compound 92a and 19 mg of title compound 92b are obtained ascolorless foams.

[0520]¹H-NMR (CD₂Cl₂/CD₃OD): 92a: δ=0.51 ppm (s, 3H); 0.89 (d, 3H); 1.27(t, 3H); 2.78 (q, 2H); 3.94 (m, 1H); 4.02 (m, 1H); 4.75 (t, 1H); 5.84(d, 1H); 6.25 (d, 1H); 6.59 (d, 1H); 6.71 (d, 1H)

[0521] 92b: δ=0.51 ppm (s, 3H); 0.90 (d, 3H); 1.27 (t, 3H); 2.78 (q,2H); 3.94 (m, 1H); 4.02 (m, 1H); 4.76 (t, 1H); 5.84 (d, 1H); 6.25 (d,1H); 6.59 (d, 1H); 6.71 (d, 1H)

Example 23

[0522](7E)-(1R,3R,24aR)-24a-[5-(2-Hydroxyethyl)-4-methylthiazol-2-yl]-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-54iol102a and(7E)-(1R,3R,24aS)-24a-[5-(2-hydroxyethyl)-4-methylthiazol-2-yl]-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol102b

[0523] 89. 2.09 ml of 5-(2-hydroxyethyl)-4-methylthiazole 93 isintroduced into 150 ml of dichloromethane, 7.8 ml of 2,3-dihydropyranand 400 mg of pyridinium-p-toluenesulfonate are added, and it is stirredfor 5 days at room temperature. Then, sodium chloride solution is added,extracted with ethyl acetate, the organic phase is washed with sodiumbicarbonate solution and sodium chloride solution, dried on sodiumsulfate and concentrated by evaporation. The residue is chromatographedon silica gel with ethyl acetate/hexane, whereby 3.8 g of5-[2-[(tetrahydro-2H-pyran-2-yl)oxy]ethyl]-4-methylthiazole 94 isobtained as a colorless oil.

[0524]¹H-NMR (CDCl₃): δ=1.48-1.90 ppm (m, 6H); 2.41 (s, 3H); 3.05 (t,2H); 3.48 (m, 1H); 3.56 (dt, 1H); 3.75 (m, 1H); 3.93 (dt, 1H); 4.61 (m,1H); 8.54 (s, 1H)

[0525] 90. 2.78 g of thiazole 94 is introduced into 25 ml oftetrahydrofuran, and 4.9 ml of n-butyllithium solution (2.5 M in hexane)is added at −78° C. After 30 minutes at this temperature, 900 mg ofaldehyde 8 in 5 ml of tetrahydrofuran is added in drops, and it isstirred for 1 more hour. Then, it is quenched with sodium chloridesolution, extracted with ethyl acetate, the organic phase is washed withsodium chloride solution and dried on sodium sulfate. The solvent isremoved, and the residue is chromatographed on silica gel with ethylacetate/hexane, whereby 1.12 g of[1R-[1α(1R*),3aβ,4α,7aα]]-α-[4-[octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1H-inden-1-yl]pentyl]-5-[2-[(tetrahydro-2H-pyran-2-yl)oxy]ethyl]-4-methylthiazol-2-methanol95 is obtained as a colorless oil.

[0526]¹H-NMR (CDCl₃): δ=0.56 ppm (q, 6H); 0.89 (d, 3H); 0.90 (s, 3H);0.96 (t, 9H); 2.32 (s, 3H); 3.00 (t, 2H); 3.48 (m, 1H); 3.58 (dt, 1H);3.75 (m, 1H); 3.90 (dt, 1H); 4.03 (m, 1H); 4.61 (m, 1H); 4.87 (m, 1H);6.6.2 (d, 1H); 6.80 (d, 1H)

[0527] 91. 1.12 q of alcohol 95 is treated analogously to 9., and 104 mgof[1R-[1α(1R*),3aβ,4α,7aα]]-5-[octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1H-inden-1-yl]-1-[5-[2-[(tetrahydro-2H-pyran-2-yl)oxy]ethyl]-4-methylthiazol-2-yl]hexyl-acetate96 is obtained as a colorless oil.

[0528]¹H-NMR (CDCl₃): δ=0.55 ppm (q, 6H); 0.88/0.89 (d, 3H); 0.90 (s,3H); 0.96 (t, 9H); 2.11 (s, 3H); 2.35 (s, 3H); 3.00 (t, 2H); 3.50. (m,1H); 3.53 (dt, 1H); 3.74 (m, 1H); 3.90 (dt, 1H); 4.02 (m, 1H); 4.61 (m,1H); 5.97 (t, 1H)

[0529] 92. 1.04 g of acetate 96 is treated analogously to 10., and 540mg of[1R-[1α(1R*),3aβ,4α,7aα]]-1-[5-(acetyloxy)-5-[5-[2-[(tetrahydro-2H-pyran-2-yl)oxy]ethyl]-4-methylthiazol-2-yl]-1-methylpentyl]octahydro-7a-methyl-1H-inden-4-ol97 is obtained as a colorless oil.

[0530]¹H-NMR (CDCl₃): δ=0.88/0.89 ppm (d, 3H); 0.91 (s, 3H); 2.11 (s,3H); 2.35 (s, 3H); 3.00 (t, 2H); 3.50 (m, 1H); 3.55 (dt, 1H); 3.74 (m,1H); 3.90 (dt, 1H); 4.07 (m, 1H); 4.61 (m, 1H); 5.97 (t, 1H)

[0531] 93. 540 mg of alcohol 97 is treated analogously to 11., and 498mg of[1R-[1α(1R*),3aβ,7aα]]-1-[5-(acetyloxy)-5-[5-[2-[(tetrahydro-2H-pyran-2-yl)oxy]ethyl]-4-methylthiazol-2-yl]-1-methylpentyl]octahydro-7a-methyl-4H-inden-4-one98 is obtained as a colorless oil.

[0532]¹H-NMR (CDCl₃): δ=0.62 ppm (s, 3H); 0.92/0.93 (d, 3H); 2.13 (s,3H); 2.37 (s, 3H); 3.00 (t, 2H); 3.49 (m, 1H); 3.54 (dt, 1H); 3.73 (m,1H); 3.90 (dt, 1H); 4.61 (m, 1H); 5.97 (t, 1H)

[0533] 94. 656 mg of phosphine oxide 13, which was deprotonated with0.55 ml of n-butyllithium solution (2.5 M in hexane), is reacted with300 mg of ketone 98 analogously to 12., and 310 mg of(7E)-(1R,3R)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-[5-[2-[(tetrahydro-2H-pyran-2-yl)oxy]ethyl]-4-methylthiazol-2-yl]-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-yl-acetate99 is obtained as a colorless foam.

[0534]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.53 (s, 3H); 0.90 (s, 18H);0.91 (d, 3H); 2.12 (s, 3H); 2.38 (s, 3H); 3.01 (t, 2H); 3.50 (m, 1H);3.56 (dt, 1H); 3.75 (m, 1H); 3.90 (dt, 1H); 4.09 (m, 2H); 4.61 (m, 1H);5.82 (d, 1H); 5.97 (t, 1H); 6.18 (d, 1H)

[0535] 95. 151 mg of acetate 99 is reacted analogously to 13., and 104mg of(7E)-(1R,3R)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]-oxy]-24a-[5-[2-[(tetrahydro-2H-pyran-2-yl)oxy]ethyl]-4-methylthiazol-2-yl]-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-ol100 is obtained as a colorless foam.

[0536]¹H-NMR (CD₂Cl₂): δ=0.04 ppm (s, 12H); 0.51 (s, 3H); 0.85 (s, 18H);0.90 (d, 3H); 2.28 (s, 3H); 2.95 (t, 2H); 3.40 (m, 1H); 3.50 (dt, 1H);3.70 (m, 1H); 3.82 (dt, 1H); 4.07 (m, 2H); 4.80 (m, 1H); 5.80 (d, 1H);6.17 (d, 1H)

[0537] 96. 170 mg of THP ether 100 is introduced into 20 ml ofdichloromethane, 0.41 ml of dimethyl aluminum chloride solution is addedat −25° C., and it is stirred for 1 more hour, whereby the mixture isheated to 0° C. Then, it is quenched with sodium bicarbonate solution,extracted with ethyl acetate, the organic phase is washed with sodiumchloride solution, dried on sodium sulfate, and the solvent is removedin a vacuum. The residue is chromatographed on silica gel with ethylacetate/hexane, whereby 153 mg of(7E)-(1R,3R)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-[5-(2-hydroxyethyl)-4-methylthiazol-2-yl]-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-ol101 is obtained as a colorless foam.

[0538]¹H-NMR (CD₂Cl₂): δ=0.04 ppm (s, 12H); 0.51 (s, 3H); 0.85 (s, 18H);0.90 (d, 3H); 2.28 (s, 3H); 2.92 (t, 2H); 3.26 (t, 2H); 4.08 (m, 2H);4.80 (m, 1H); 5.80 (d, 1H); 6.17 (d, 1H)

[0539] 97. 113 mg of alcohol 101 is treated analogously to 14., andafter the diastereomers (in terms of C-24a) are separated by HPLC, 21 mgof title compound 102a and 24 mg of title compound 102b are obtained ascolorless foams.

[0540]¹H-NMR (CD₂Cl₂/CD₃OD): 102a: δ=0.50 ppm (s, 3H); 0.88 (d, 3H);2.27 (s, 3H); 2.88 (t, 2H); 3.68 (d, 2H); 3.92 (m, 1H); 4.00 (m, 1H);4.74 (m, 1H); 5.82 (d, 1H); 6.24 (d, 1H)

[0541] 102b: δ=0.50 ppm (s, 3H); 0.89 (d, 3H); 2.28 (s, 3H); 2.88 (t,2H); 3.68 (d, 2H); 3.92 (m, 1H); 4.00 (m, 1H); 4.75 (dd, 1H); 5.82 (d,1H); 6.24 (d, 1H)

Example 24

[0542](7E)-(1R,3R)-1,3-Dihydroxy-24a-[5-(2-hydroxyethyl)-4-methylthiazol-2-yl]-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one104

[0543] 98. 70 mg of alcohol 100 is treated analogously to 25., whereby40 mg of(7E)-(1R,3R)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]-oxy]-24a-[5-(2-hydroxyethyl)-4-methylthiazol-2-yl]-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one103 accumulates as a colorless foam.

[0544]¹H-NMR (CD₂Cl₂): δ=0.04 ppm (s, 12H); 0.51 (s, 3H) 0.84 (s, 18H);0.93 (d, 3H); 2.37 (s, 3H); 3.01 (t, 2H); 3.40 (m, 1H); 3.53 (dt, 1H);3.68 (m, 1H); 3.89 (dt, 1H); 4.08 (m, 2H); 4.54 (m, 1H); 5.80 (d, 1H);6.15 (d, 1H)

[0545] 99. 40 mg of ketone 103 is treated analogously to 26., whereby 12mg of title compound 104 accumulates as a colorless foam.

[0546]¹H-NMR (CD₂Cl₂): δ=0.52 ppm (s, 3H); 0.95 (d, 3H); 2.41 (s, 3H);3.01 (t, 2H); 3.80 (t, 2H); 3.95 (m, 1H); 4.05 (m, 1H); 5.82 (d, 1H);6.25 (d, 1H)

Example 25

[0547](7E)-(1R,3R,24aR)-24a-(Benzothiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol111a and(7E)-(1R,3R,24aS)-24a-(benzothiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol111b

[0548] 100. 0.85 ml of benzothiazole is introduced into 20 ml oftetrahydrofuran, and 3.1 ml of n-butyllithium solution (2.5 M in hexane)is added at −78° C. After 30 minutes at this temperature, 574 mg ofaldehyde 8 in 3 ml of tetrahydrofuran is added in drops, and it isstirred for 1 more hour. Then, it is quenched with sodium chloridesolution, extracted with ethyl acetate, the organic phase is washed withsodium chloride solution and dried on sodium sulfate. The solvent isremoved, and the residue is chromatographed on silica gel with ethylacetate/hexane, whereby 751 mg of[1R-[1α(1R*),3aβ,4α,7aα]]-α-[4-[octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1H-inden-1-yl]pentyl]benzothiazol-2-methanol105 is obtained as a colorless oil.

[0549]¹H-NMR (CDCl₃): δ=0.55 ppm (q, 6H); 0.89 (d, 3H); 0.91 (s, 3H);0.95 (t, 9H); 4.02 (m, 1H); 5.10 (m, 1H); 7.40 (t, 1H); 7.48 (t, 1H);7.90 (d, 1H); 8.00 (d, 1H)

[0550] 101. 751 mg of alcohol 105 is treated analogously to 9., and 764mg of[1R-[1α(1R*),3aβ,4α,7aα]]-1-(benzothiazol-2-yl)-5-[octahydro-7a-methyl-4-[(triethyl-silyl)oxy]-1H-inden-1-yl)hexyl-acetate106 is obtained as a colorless oil.

[0551]¹H-NMR (CDCl₃): δ=0.55 ppm (q, 6H); 0.88/0.89 (d, 3H); 0.90 (s,3H); 0.96 (t, 9H); 2.20 (s, 3H); 4.02 (m, 1H); 6.15 (t, 1H); 7.40 (t,1H); 7.49 (t, 1H); 7.90 (d, 1H); 8.03 (d, 1H)

[0552] 102. 764 mg of acetate 106 is treated analogously to 10., and 310mg of[1R-[1α(1R*),3aβ,4α,7aα]]-1-5-(acetyloxy)-5-(benzothiazol-2-yl)-1-methylpentyl]octahydro-7a-methyl-1H-inden-4-ol107 is obtained as a colorless oil.

[0553]¹H-NMR (CDCl₃): δ=0.88/0.89 ppm (d, 3H); 0.91 (s, 3H); 2.19 (s,3H); 4.07 (m, 1H); 6.17 (t, 1H); 7.40 (t, 1H); 7.49 (t, 1H); 7.90 (d,1H); 8.03 (d, 1H)

[0554] 103. 310 mg of alcohol 107 is treated analogously to 11., and 277mg of[1R-[1α(1R*),3aβ,7aα]]-1-[5-(acetyloxy)-5-(benzothiazol-2-yl)-1-methylpentyl]octahydro-7a-methyl-4H-inden-4-one108 is obtained as a colorless oil.

[0555]¹H-NMR (CDCl₃): δ=0.62 ppm (s, 3H); 0.92/0.93 (d, 3H); 2.19 (s,3H); 6.17 (t, 1H); 7.40 (t, 1H); 7.49 (t, 1H); 7.89 (d, 1H); 8.02 (d,1H)

[0556] 104. 736 mg of phosphine oxide 13, which was deprotonated with0.62 ml of n-butyllithium solution (2.5 M in hexane), is reacted with277 mg of ketone 108 analogously to 12., and 193 mg of(7E)-(1R,3R)-24a-(acetyloxy)-24a-(2-benzothiazol-2-yl)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-homo-19-nor-9,10-secochola-5,7-diene109 is obtained as a colorless foam.

[0557]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.53 (s, 3H); 0.90 (s, 18H);0.91 (d, 3H); 2.19 (s, 3H); 4.08 (m, 2H); 5.82 (d, 1H); 6.18 (d, 1H);6.18 (m, 1H); 7.38 (t, 1H); 7.49 (t, 1H); 7.88 (d, 1H); 8.02 (d, 1H)

[0558] 105. 193 mg of acetate 109 is reacted analogously to 13., and 177mg of(7E)-(1R,3R)-24a-(benzothiazol-2-yl)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-ol110 is obtained as a colorless foam.

[0559]¹H-NMR (CD₂Cl₂): δ=0.04 ppm (s, 12H); 0.51 (s, 3H); 0.86 (s, 18H);0.92 (d, 3H); 4.06 (m, 2H); 5.04 (m, 1H); 5.80 (d, 1H); 6.16 (d, 1H);7.33 (t, 1H); 7.43 (t, 1H); 7.87 (d, 1H); 7.92 (d, 1H)

[0560] 106. 124 mg of alcohol 110 is treated analogously to 14., andafter the diastereomers (in terms of C-24a) are separated by HPLC, 23 mgof title compound 111a and 22-mg of title compound 111b are obtained ascolorless foams.

[0561]¹H-NMR (CD₂Cl₂): 111a: δ=0.50 ppm (s, 3H); 0.90 (d, 3H); 3.95 (m,1H); 4.02 (m, 1H); 5.07 (m, 1H); 5.82 (d, 1H); 6.24 (d, 1H); 7.36 (t,1H); 7.46 (t, 1H); 7.90 (d, 1H); 7.93 (d, 1H)

[0562] 111b: δ=0.51 ppm (s, 3H); 0.91 (d, 3H); 3.95 (m, 1H); 4.02 (m,1H); 5.06 (m, 1H); 5.82 (d, 1H); 6.24 (d, 1H); 7.36 (t, 1H); 7.46 (t,1H); 7.90 (d, 1H); 7.93 (d, 1H)

Example 26

[0563](7E)-(1R,3R)-24a-(Benzothiazol-2-yl)-1,3-dihydroxy-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one113

[0564] 107. 53 mg of alcohol 110 is treated analogously to 25., whereby39 mg of(7E)-(1R,3R)-24a-(benzothiazol-2-yl)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one112 accumulates as a colorless foam.

[0565]¹H-NMR (CD₂Cl₂) δ=0.04 ppm (s, 12H); 0.52 (s, 3H); 0.85 (s, 18H);0.96 (d, 3H); 4.06 (m, 2H); 4.54 (m, 1H); 5.80 (d, 1H); 6.15 (d, 1H);7.25 (t, 1H); 7.59 (t, 1H); 8.01 (d, 1H); 8.15 (d, 1H)

[0566] 108. 39 mg of ketone 112 is treated analogously to 26., whereby20 mg of title compound 113 accumulates as a colorless foam.

[0567]¹H-NMR (CD₂Cl₂): δ=0.53 ppm (s, 3H); 0.95 (d, 3H); 3.94 (m, 1H);4.02 (m, 1H); 5.82 (d, 1H); 6.25 (d, 1H); 7.53 (t, 1H); 7.56 (t, 1H);7.98 (d, 1H); 8.13 (d, 1H)

Example 27

[0568](7E)-(1R,3R,24aR)-24a-(Benzofuran-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol120a and(7E)-(1R,3R,24aS)-24a-(benzofuran-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol120b

[0569] 109. 1.44 mg of 2,3-benzofuran is introduced into 25 ml oftetrahydrofuran, and 5.2 ml of n-butyllithium solution (2.5 M in hexane)is added at −78° C. After 30-minutes at this temperature, 960 mg ofaldehyde 8 in 5 ml of tetrahydrofuran is added in drops, and it isstirred for 1 more hour. Then, it is quenched with sodium chloridesolution, extracted with ethyl acetate, the organic phase is washed withsodium chloride solution and dried on sodium sulfate. The solvent isremoved, and the residue is chromatographed on silica gel with ethylacetate/hexane, whereby 1.06 g of[1R-[1α(1R*),3aβ,4α,7aα]]-α-[4-[octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1H-inden-1-yl]pentyl]benzofuran-2-methanol114 is obtained as a colorless oil.

[0570]¹H-NMR (CDCl₃): δ=0.56 ppm (q, 6H); 0.89 (d, 3H); 0.91 (s, 3H);0.95 (t, 9H); 4.02 (m, 1H); 4.83 (m, 1H); 7.22 (t, 1H); 7.29 (t, 1H);7.48 (d, 1H); 7.57 (d, 1H)

[0571] 110. 1.06 g of alcohol 114 is introduced into 18 ml ofdichloromethane, and 0.83 ml of 2,3-dihydropyran and 48 mg ofpyridinium-p-toluene sulfonate are added. It is stirred for 1 day atroom temperature, and then sodium chloride solution is added. It isextracted with ethyl acetate, the organic phase is washed with sodiumchloride solution, dried on sodium sulfate and concentrated byevaporation. The residue is chromatographed on silica gel with ethylacetate/hexane, whereby 1.11 q of[1R[1α(1R*),3aβ,4α,7aα]]-1-[5-(benzofuran-2-yl)-1-methyl-5-[(tetrahydro-2H-pyran-2-yl)oxy]pentyl]octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1H-indene115 is obtained as a colorless oil.

[0572]¹H-NMR (CDCl₃): δ=0.55 ppm (q, 6H); 0.88/0.89 (d, 3H); 0.90 (s,3H); 0.96 (t, 9H); 3.40 (m, 1H); 3.55 (m, 1H); 4.02 (m, 1H); 4.77 (t,1H); 6.65 (m, 1H); 7.23 (m, 2H); 7.49 (d, 1H); 7.54 (d, 1H)

[0573] 111. 1.11 g of silyl ether 115 is introduced into 50 ml oftetrahydrofuran, 1.81 g of tetrabutylammonium fluoride is added, and itis stirred for 1 day at room temperature. Then, sodium chloride solutionis added, extracted with ethyl acetate, washed with sodium chloridesolution, dried on sodium sulfate and concentrated by evaporation. Theresidue is chromatographed on silica gel with ethyl acetate/hexane,whereby 760 mg of[1R[1α(1R*),3aβ,4α,7aα]]-1-[5-(benzofuran-2-yl)-1-methyl-5-[(tetrahydro-2H-pyran-2-yl)oxy]pentyl]octahydro-7a-methyl-1H-inden-4-ol116 is obtained as a colorless oil.

[0574]¹H-NMR (CDCl₃): δ=0.88/0.89 ppm (d, 3H); 0.91 (s, 3H); 3.40 (m,1H); 3.55 (m, 1H); 4.04 (m, 1H); 4.60 (m, 1H); 4.78 (t, 1H); 6.65 (m,1H); 7.25 (m, 2H); 7.48 (d, 1H); 7.55 (d, 1H)

[0575] 112. 750 mg of alcohol 116 is treated analogously to 11., and 669mg of[1R-[1α(1R*),3aβ,7aα]]-1-[5-(benzofuran-2-yl)-1-methyl-5-[(tetrahydro-2H-pyran-2-yl)oxy]pentyl]octahydro-7a-methyl-4H-inden-4-one117 is obtained as a colorless oil.

[0576]¹H-NMR (CDCl₃): δ=0.62 ppm (s, 3H); 0.92/0.93 (d, 3H); 3.40 (m,1H); 3.54 (m, 1H); 4.60 (m, 1H); 4.80 (t, 1H); 6.65 (m, 1H); 7.25 (m,2H); 7.49 (d, 1H); 7.55 (d, 1H)

[0577] 113. 314 mg of THP-ether 117 is introduced into 10 ml ofmethanol, and 244 mg of pyridinium-p-toluenesulfonate is added. It isstirred for 1 hour at room temperature and then treated with sodiumchloride solution. It is extracted with ethyl acetate, the organic phaseis washed with sodium bicarbonate solution and sodium chloride solution,dried on sodium sulfate and concentrated by evaporation. The residue ischromatographed on silica gel with ethyl acetate/hexane, whereby 760 mgof[1R[1α(1R*),3aβ,7aα]]-1-[5-(benzofuran-2-yl)-5-hydroxy-1-methylpentyl]octahydro-7a-methyl-4H-inden-4-one118 is obtained as a colorless oil.

[0578]¹H-NMR (CDCl₃): δ=0.62 ppm (s, 3H); 0.92/0.93 (d, 3H); 4.81 (m,1H); 6.61 (s, 1H); 7.22 (t, 1H); 7.28 (t, 1H); 7.47 (d, 1H); 7.54 (d,1H)

[0579] 114. 180 mg of alcohol 118 is treated analogously to 9., and 169mg of[1R-[1α(1R*),3aβ,7aα]]-1-[5-(acetyloxy)-5-(benzofuran-2-yl)-1-methylpentyl]octahydro-7a-methyl-4H-inden-4-one119 is obtained as a colorless oil.

[0580]¹H-NMR (CDCl₃): δ=0.62 ppm (s, 3H); 0.92/0.93 (d, 3H); 2.10 (s,3H); 5.97 (m, 1H); 6.69 (s, 1H); 7.23 (t, 1H); 7.30 (t, 1H); 7.50 (d,1H); 7.55 (d, 1H)

[0581] 115. 444 mg of phosphine oxide 13, which was deprotonated with0.37 ml of n-butyllithium solution (2.5 M in hexane), is reacted with160 mg of ketone 119 analogously to 12., and 189 mg of(7E)-(1R,3R)-24a-(acetyloxy)-24a-(2-benzofuran-2-yl)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-homo-19-nor-9,10-secochola-5,7-diene120 is obtained as a colorless foam.

[0582]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.53 (s, 3H); 0.90 (s, 18H);0.91 (d, 3H); 2.10 (s, 3H); 4.08 (m, 2H); 5.81 (d, 1H); 5.97 (t, 1H);6.18 (m, 1H); 6.70 (s, 1H); 7.22 (t, 1H); 7.30 (t, 1H); 7.49 (d, 1H);7.55 (d, 1H)

[0583] 116. 142 mg-of acetate 120 is reacted analogously to 13., and 134mg of(7E)-(1R,3R)-24a-(benzothiazol-2-yl)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-ol121 is obtained as a colorless foam.

[0584]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.53 (s, 3H); 0.89 (s, 18H);0.94 (d, 3H); 4.08 (m, 2H); 4.83 (m, 1H); 5.82 (d, 1H); 6.18 (d, 1H);6.62 (s, 1H); 7.22 (t, 1H); 7.28 (t, 1H); 7.47 (d, 1H); 7.55 (d, 1H)

[0585] 117. 134 mg of alcohol 121 is treated analogously to 14., andafter the diastereomers (in terms of C-24a) are separated by HPLC, 29 mgof title compound 122a and 26 mg of title compound 122b are obtained ascolorless foams.

[0586]¹H-NMR (CD₂Cl₂/CD₃OD): 122a: δ=0.50 ppm (s, 3H); 0.88 (d, 3H);3.92 (m, 1H); 4.00 (m, 1H); 4.71 (t, 1H); 5.81 (d, 1H); 6.22 (d, 1H);6.58 (s, 1H); 7.18 (t, 1H); 7.21 (t, 1H); 7.41 (d, 1H); 7.52 (d, 1H)

[0587] 122b: δ=0.50 ppm (s, 3H); 0.89 (d, 3H); 3.92 (m, 1H); 4.00 (m,1H); 4.72 (t, 1H); 5.81 (d, 1H); 6.22 (d, 1H); 6.58 (s, 1H); 7.18 (t,1H); 7.21 (t, 1H); 7.41 (d, 1H); 7.53 (d, 1H)

Example 28

[0588](7E)-(1R,3R)-24a-(Benzofuran-2-yl)-1,3-dihydroxy-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one124

[0589] 118. 49 mg of alcohol 121 is treated analogously to 25., whereby39 mg of(7E)-(1R,3R)-24a-(benzofuran-2-yl)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one123 accumulates as a colorless foam.

[0590]¹H-NMR (CD₂Cl₂): δ=0.04 ppm (s, 12H); 0.52 (s, 3H); 0.85 (s, 18H);0.97 (d, 3H); 4.06 (m, 2H); 4.54 (m, 1H); 5.81 (d, 1H); 6.16 (d, 1H);7.29 (t, 1H); 7.46 (t, 1H); 7.47 (s, 1H); 7.59 (d, 1H); 7.72 (d, 1H)

[0591] 119. 39 mg of ketone 123 is treated analogously to 26., whereby12 mg of title compound 124 accumulates as a colorless foam.

[0592]¹H-NMR (CD₂Cl₂): δ=0.53 ppm (s, 3H); 0.95 (d, 3H); 3.95 (m, 1H);4.03 (m, 1H); 5.84 (d, 1H); 6.25 (d, 1H); 7.30 (t, 1H); 7.46 (t, 1H);7.49 (s, 1H); 7.56 (d, 1H); 7.72 (d, 1H)

Example 29

[0593](7E)-(1R,3R,24aR)-24a-(Benzothiophen-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol131a and(7E)-(1R,3R,24aS)-24a-(benzothiophen-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol131b

[0594] 120. 0.79 ml of 1-benzothiophene is introduced into 12 ml oftetrahydrofuran, and 2.72 ml of n-butyllithium solution (2.5 M inhexane) is added at −78° C. After 30 minutes at this temperature, 500 mgof aldehyde 8 in 3 ml of tetrahydrofuran is added in drops, and it isstirred for 1 more hour. Then, it is quenched with sodium chloridesolution, extracted with ethyl acetate, the organic phase is washed withsodium chloride solution and dried on sodium sulfate. The solvent isremoved, and the residue is chromatographed on silica gel with ethylacetate/hexane, whereby 679 mg of[1R-[1α(1R*),3aβ,4α,7aα]]-α-[4-[octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1H-inden-1-yl]pentyl]benzothiophene-2-methanol125 is obtained as a colorless oil.

[0595]¹H-NMR (CDCl₃): δ=0.56 ppm (q, 6H); 0.89 (d, 3H); 0.91 (s, 3H);0.96 (t, 9H); 4.03 (m, 1H); 5.02 (m, 1H); 7.36 (m, 3H); 7.45 (d, 1H);7.88 (d, 2H)

[0596] 121. 670 mg of alcohol 125 is treated analogously to 9., and 699mg of[1R-[1α(1R*),3aβ,4α,7aα]]-1-(benzothiophen-2-yl)-5-[octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1H-inden-1-yl)hexyl-acetate126 is obtained as a colorless oil.

[0597]¹H-NMR (CDCl₃): δ=0.55 ppm (q, 6H); 0.88/0.89 (d, 3H); 0.90 (s,3H); 0.95 (t, 9H); 2.10 (s, 3H); 4.02 (m, 1H); 6.10 (t, 1H); 7.33 (m,3H); 7.75 (d, 1H); 7.81 (d, 1H)

[0598] 122. 336 mg of acetate 126 is treated analogously to 10., and 221mg of[1R-[1α(1R*),3aβ,4,7aα]]-1-[5-(acetyloxy)-5-(benzothiophen-2-yl)-1-methylpentyl]octahydro-7a-methyl-1H-inden-4-ol127 is obtained as a colorless oil.

[0599]¹H-NMR (CDCl₃): δ=0.88/0.89 ppm (d, 3H); 0.91/0.92 (s, 3H); 2.10(s, 3H); 4.07 (m, 1H); 6.10 (t, 1H); 7.33 (m, 3H); 7.74 (d, 1H); 7.81(d, 1H)

[0600] 123. 215 mg of alcohol 127 is treated analogously to 11., and 195mg of[1R-[1α(1R*),3aβ,7aα]]-1-[5-(acetyloxy)-5-(benzothiophen-2-yl)-1-methylpentyl]octahydro-7a-methyl-4H-inden-4-one128 is obtained as a colorless oil.

[0601]¹H-NMR (CDCl₃): δ=0.62 ppm (s, 3H); 0.92/0.93 (d, 3H); 2.10 (s,3H); 6.10 (t, 1H); 7.35 (m, 3H); 7.73 (d, 1H); 7.82 (d, 1H)

[0602] 124. 480 mg of phosphine oxide 13., which was deprotonated with0.4 ml of n-butyllithium solution (2.5 M in hexane), is reacted with 180mg of ketone 128 analogously to 12., and 266 mg of(7E)-(1R,3R)-24a-(acetyloxy)-24a-(2-benzothiophen-2-yl)-1,3-bis[[(1,1-dimethylethyl)dimethyl-silyl]oxy]-24a-homo-19-nor-9,10-secochola-5,7-diene129 is obtained as a colorless foam.

[0603]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.53 (s, 3H); 0.90 (s, 18H);0.91 (d, 3H); 2.10 (s, 3H); 4.08 (m, 2H); 5.80 (d, 1H); 6.10 (t, 1H);6.18 (m, 1H); 7.33 (m, 2H); 7.72 (d, 1H); 7.82 (d, 1H)

[0604] 125. 260 mg of acetate 129 is reacted analogously to 13., and 228mg of(7E)-(1R,3R)-24a-(benzothiophen-2-yl)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-ol130 is obtained as a colorless foam.

[0605]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.53 (s, 3H); 0.89 (s, 18H);0.93 (d, 3H); 4.08 (m, 2H); 5.00 (m, 1H); 5.82 (d, 1H); 6.19 (d, 1H);7.21 (s, 1H) 7.33 (m, 2H); 7.73 (d, 1H); 7.83 (d, 1H)

[0606] 126. 172 mg of alcohol 130 is treated analogously to 14., andafter the diastereomers (in terms of C-24a) are separated by HPLC, 22 mgof title compound 131a and 24 mg of title compound 131b are obtained ascolorless foams.

[0607]¹H-NMR (CD₂Cl₂/CD₃OD): 131a: δ=0.50 ppm (s, 3H); 0.88 (d, 3H);3.92 (m, 1H); 4.00 (m, 1H); 4.90 (t, 1H); 5.81 (d, 1H); 6.22 (d, 1H);7.16 (s, 1H); 7.26 (t, 1H); 7.28 (t, 1H); 7.68 (d, 1H); 7.77 (d, 1H)

[0608] 131b: δ=0.50 ppm (s, 3H); 0.89 (d, 3H); 3.92 (m, 1H); 4.00 (m,1H); 4.91 (t, 1H); 5.81 (d, 1H); 6.22 (d, 1H); 7.16 (s, 1H); 7.26 (t,1H); 7.27 (t, 1H); 7.68 (d, 1H); 7.77 (d, 1H)

Example 30

[0609](7E)-(1R,3R)-24a-(Benzothiophen-2-yl)-1,3-dihydroxy-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one133

[0610] 127. 50 mg of alcohol 130 is treated analogously to 25., whereby38 mg of(7E)-(1R,3R)-24a-(benzothiophen-2-yl)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one132 accumulates as a colorless foam.

[0611]¹H-NMR (CD₂Cl₂): δ=0.04 ppm (s, 12H); 0.52 (s, 3H); 0.85 (s, 18H);0.96 (d, 3H); 4.05 (m, 2H); 5.82 (d, 1H); 6.16 (d, 1H); 7.41 (t, 1H);7.46 (t, 1H); 7.88 (d, 1H); 7.91 (d, 1H); 7.95 (s, 1H)

[0612] 128. 38 mg of ketone 132 is treated analogously to 26., whereby21 mg of title compound 133 accumulates as a colorless foam.

[0613]¹H-NMR (CD₂Cl₂): δ=0.53 ppm (s, 3H); 0.97 (d, 3H); 3.96 (m, 1H);4.03 (m, 1H); 5.84 (d, 1H); 6.26 (d, 1H); 7.39 (t, 1H); 7.46 (t, 1H);7.88 (d, 1H); 7.90 (d, 1H); 7.97 (s, 1H)

Example 31

[0614](7E)-(R,3R,24aR)-24a-(1-Methylbenzimidazol-2-yl)-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol140a and(7E)-(1R,3R,24aS)-24a-(1-methylbenzimidazol-2-yl)-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol140b

[0615] 129. 899 mg of 1-methylbenzimidazole is introduced into 12 ml oftetrahydrofuran, and 2.72 ml of n-butyllithium solution (2.5 M inhexane) is added at −78° C. After 30 minutes at this temperature, 500 mgof aldehyde 8 in 3 ml of tetrahydrofuran is added in drops, and it isstirred for 1 more hour. Then, it is quenched with sodium chloridesolution, extracted with ethyl acetate, the organic phase is washed withsodium chloride solution and dried on sodium sulfate. The solvent isremoved, and the residue is chromatographed on silica gel with ethylacetate/hexane, whereby 487 mg of[1R-[1α(1R*),3aβ,4α,7a]]-α-[4-[octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1H-inden-1-yl]pentyl]-1-methylbenzimidazole-2-methanol134 is obtained as a colorless oil.

[0616]¹H-NMR (CDCl₃): δ=0.56 ppm (q, 6H); 0.89 (d, 3H); 0.91 (s, 3H);0.96 (t, 9H); 3.78 (s, 3H); 4.02 (m, 1H); 4.93 (m, 1H); 7.25 (m, 3H);7.71 (d, 1H)

[0617] 130. 480 mg of alcohol 134 is treated analogously to 9., and 382mg of[1R-[1α(1R*),3aβ,4α,7aα]]-5-octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1H-inden-1-yl]-1-(1-methylbenzimidazol-2-yl)hexyl-acetate135 is obtained as a colorless oil.

[0618]¹H-NMR (CDCl₃): δ=0.56 ppm (q, 6H); 0.88/0.89 (d, 3H); 0.90 (s,3H); 0.95 (t, 9H); 2.11 (s, 3H); 3.87 (s, 3H); 4.02 (m, 1H); 6.02 (t,1H); 7.32 (m, 3H); 7.80 (d, 1H)

[0619] 131. 375 mg of acetate 135 is treated analogously to 10., and 259mg of[1R-[1α(1R*),3aβ,4α,7aα]]-1-[5-(acetyloxy)-1-methyl-5-(1-methylbenzimidazol-2-yl)pentyl]octahydro-7a-methyl-1H-inden-4-ol136 is obtained as a colorless oil.

[0620]¹H-NMR (CDCl₃): δ=0.88/0.89 ppm (d, 3H); 0.91/0.92 (s, 3H); 2.11(s, 3H); 3.88 (s, 3H); 4.07 (m, 1H); 6.03 (t, 1H); 7.32 (m, 3H); 7.79(d, 1H)

[0621] 132. 250 mg of alcohol 136 is treated analogously to 11., and 118mg of[1R-[1α(1R*),3aβ,7aα]]-1-[5-(acetyloxy)-1-methyl-5-(1-methylbenzimidazol-2-yl)pentyl]octahydro-7a-methyl-4H-inden-4-one137 is obtained as a colorless oil.

[0622]¹H-NMR (CDCl₃): δ=0.62/0.63 ppm (s, 3H); 0.92/0.93 (d, 3H); 2.14(s, 3H); 3.88 (e, 3H); 6.03 (t, 1H); 7.32 (m, 3H); 7.80 (d, 1H)

[0623] 133. 317 mg of phosphine oxide 13, which was deprotonated with0.27 ml of n-butyllithium solution (2.5 M in hexane), is reacted with118 mg of ketone 137 analogously to 12., and 208 mg of(7E)-(1R,3R)-24a-(acetyloxy)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-(1-methylbenzimidazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene138 is obtained as a colorless foam.

[0624]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.52 (s, 3H); 0.90 (s, 18H);0.91 (d, 3H); 2.10 (s, 3H); 3.85 (s, 3H); 4.08 (m, 2H); 5.80 (d, 1H);6.02 (t, 1H); 6.16 (d, 1H); 7.33 (m, 3H); 7.78 (d, 1H)

[0625] 134. 218 mg of acetate 138 is reacted analogously to 13., and 167mg of(7E)-(1R,3R)-1,3-bis[[dimethyl(1,1-dimethylethyl)silyl]oxy]-24a-(1-methylbenzimidazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-ol139 is obtained as a colorless foam.

[0626]¹H-NMR (CD₂Cl₂): δ=0.04 ppm (s, 12H); 0.50 (s, 3H); 0.85 (s, 18H);0.90 (d, 3H); 3.73 (s, 3H); 4.06 (m, 2H); 4.89 (m, 1H); 5.80 (d, 1H);6.15 (d, 1H); 7.22 (m, 3H); 7.60 (m, 1H)

[0627] 135. 115 mg of alcohol 139 is treated analogously to 14., andafter the diastereomers (in terms of C-24a) are separated by HPLC, 23 mgof title compound 140a and 22 mg of title compound 140b are obtained ascolorless foams.

[0628]¹H-NMR (CD₂Cl₂): 140a: δ=0.50 ppm (s, 3H); 0.88 (d, 3H); 3.72 (s,3H); 3.96 (m, 1H); 4.02 (m, 1H); 4.88 (t, 1H); 5.82 (d, 1H); 6.23 (d,1H); 7.23 (m, 3H); 7.62 (d, 1H)

[0629] 140b: δ=0.50 ppm (s, 3H); 0.89 (d, 3H); 3.72 (s, 3H); 3.96 (m,1H); 4.02 (m, 1H); 4.89 (t, 1H); 5.82 (d, 1H); 6.23 (d, 1H); 7.23 (m,3H); 7.62 (d, 1H)

Example 32

[0630](7E)-(1R,3R)-1,3-Dihydroxy-24a-(1-methylbenzimidazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one142

[0631] 136. 45 mg of alcohol 139 is treated analogously to 25., whereby26 mg of(7E)-(1R,3R)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]-oxy]-24a-(1-methylbenzimidazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one141 accumulates as a colorless foam.

[0632]¹H-NMR (CD₂Cl₂): δ=0.04 ppm (s, 12H); 0.52 (s, 3H); 0.86 (s, 18H);0.97 (d, 3H); 3.81 (s, 3H); 4.07 (m, 2H); 5.82 (d, 1H); 6.16 (d, 1H);7.32 (t, 1H); 7.43 (m, 2H); 7.80 (d, 1H)

[0633] 137. 26 mg of ketone 141 is treated analogously to 26., whereby 8mg of title compound 142 accumulates as a colorless foam.

[0634]¹H-NMR (CD₂Cl₂): δ=0.53 ppm (s, 3H); 0.97 (d, 3H); 3.82 (s, 3H);3.96 (m, 1H); 4.03 (m, 1H); 4.05 (s, 3H); 5.84 (d, 1H); 6.26 (d, 1H);7.31 (t, 1H); 7.43 (m, 2H); 7.80 (d, 1H)

Example 33

[0635](7E)-(1R,3R)-1-(1,3-Dihydroxy-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-yl)-3-[(4-methoxyphenyl)methoxy]-1H-pyrazole-4-carboxylicacid ethyl ester 153

[0636] 138. 10.1 ml of ethoxymethylene malonic acid diethyl ester 143and 3.3 ml of hydrazine are introduced into 100 ml of ethanol and heatedto boiling for 1 hour. After cooling, sodium chloride solution is added,extracted with ethyl acetate, the organic phase is washed with sodiumchloride solution, dried on sodium sulfate, and the solvent is removed.The residue is chromatographed on silica gel with ethyl acetate/hexane,whereby 11.2 g of ethoxymethylene malonic acid-ethyl ester hydrazide 144is obtained as a colorless oil.

[0637]¹H-NMR (CDCl₃/CD₃OD): δ=1.25 ppm (t, 3H); 1.29 (t, 3H); 3.78 (sbr,1H); 4.12 (q, 2H); 4.23 (q, 2H); 8.18 (s, 1H)

[0638] 139. 11.2 g of hydrazide 144 is treated with 30 ml of aqueoussodium hydroxide solution (25%) and stirred for 1 hour at roomtemperature. Then, it is neutralized with dilute hydrochloric acid,extracted with ethyl acetate, the organic phase is washed with sodiumchloride solution, dried on sodium sulfate and concentrated byevaporation. The residue is chromatographed on silica gel with ethylacetate/hexane, whereby 2.6 g of 3-hydroxypyrazole-4-carboxylic acidethyl ester 145 is obtained as a colorless oil.

[0639]¹H-NMR (CDCl₃/CD₃OD): δ=1.25 ppm (t, 3H); 4.20 (q, 2H); 4.25 (sbr,1H); 7.63 (s, 1H)

[0640] 140. 516 mg of sodium hydride (80% suspension) is introduced into10 ml of tetrahydrofuran/dimethylformamide (1:1), and pyrazole 145 in 1ml of tetrahydrofuran/dimethylformamide (1:1) is added in drops. It isstirred for 10 more minutes, and then 2.3 ml of p-methoxybenzyl bromideis added. It is heated to boiling for 4 hours, and then after cooling,sodium chloride solution is added, extracted with ethyl acetate, theorganic phase is washed with sodium chloride solution, dried on sodiumsulfate, and the solvent is removed. The residue is chromatographed onsilica gel with ethyl acetate/hexane, whereby 1.6 g of3-hydroxy-1-[(4-methylphenyl)methyl]pyrazole-4-carboxylic acid ester 146and 600 mg of 3-[[(4-methoxyphenyl)methyl]oxy]pyrazole-4-carboxylic acidethyl ester 147 are obtained in succession as colorless oils.

[0641]¹H-NMR (CDCl₃): 146: δ=1.27 ppm (t, 3H); 3.80 (s, 3H); 4.22 (q,2H); 5.04 (s, 2H); 7.18 (d, 2H); 7.41 (d, 2H); 7.60 (s, 1H)

[0642] 147: δ=1.30 ppm (t, 3H); 3.80 (s, 3H); 4.28 (q, 2H); 5.30 (s,2H); 6.89 (d, 2H); 7.42 (d, 2H); 7.88 (s, 1H)

[0643] 141. 540 mg of alcohol 7 is introduced into 30 ml ofdichloromethane, and 0.4 ml of triethylamine and 0.24 ml ofmethanesulfonyl chloride are added at 0° C. It is stirred for 1 hour at0° C., then sodium chloride solution is added, extracted withdichloromethane, the organic phase is washed with sodium chloridesolution, dried on sodium sulfate, and the solvent is removed, whereby510 mg of[1R-[1α(1R*),3aβ,4α,7aα]]-5-[octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1H-inden-1-yl]hexyl(methylsulfonate)148 accumulates as a yellowish oil, which is further reacted in crudeform.

[0644] 142. 36 mg of sodium hydride (80% suspension) is introduced into10 ml of dimethylformamide, and 240 mg of mesylate 148 and 88 mg ofsodium iodide are added at 0° C. After 30 minutes, it is added to benzylether 147 in 2 ml of dimethylformamide, and stirring is continuedovernight at room temperature. Then, it is quenched with sodium chloridesolution, extracted with ethyl acetate, washed with sodium chloridesolution, dried on sodium sulfate, and the solvent is removed. Theresidue is chromatographed on silica gel with ethyl acetate/hexane,whereby 580 mg of[1R[1α(1R*),3aβ,4α,7aα]]-1-[5-[octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1H-inden-1-yl]hexyl]-3-[(4-methoxyphenyl)methoxy]-1H-pyrazole-4-carboxylicacid ethyl ester 149 is obtained as a colorless oil.

[0645]¹H-NMR (CDCl₃): δ=0.55 ppm (q, 6H); 0.88/0.89 (d, 3H); 0.90 (s,3H); 0.96 (t, 9H); 1.33 (t, 3H); 3.80 (s, 3H); 3.92 (t, 2H); 4.03 (m,1H); 4.24-(q, 2H); 5.22 (s, 2H); 6.90 (d, 2H); 7.42 (d, 2H); 7.69 (s,1H)

[0646] 143. 500 mg of silyl ether 149 is introduced into 50 ml oftetrahydrofuran, and 262 mg of tetrabutylammonium fluoride (hydrate) isadded to it. It is stirred for 24 hours at room temperature and thendiluted with sodium chloride solution. It is extracted with ethylacetate, the organic phase is washed with sodium chloride solution,dried on sodium sulfate, and the solvent is removed. The residue ischromatographed on silica gel with ethyl acetate/hexane, whereby 183 mgof[1R[1α(1R*),3aβ,4α,7aα]]-1-[5-(octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl]hexyl]-3-[(4-methoxyphenyl)methoxy]-1H-pyrazole-4-carboxylicacid ethyl ester 150 is obtained as a colorless oil.

[0647]¹H-NMR (CD₂Cl₂): δ=0.88 ppm (d, 3H); 0.91 (s, 3H); 1.28 (t, 3H);3.78 (s, 3H); 3.90 (t, 2H); 4.03 (m, 1H); 4.22 (q, 2H); 5.18 (s, 2H);6.88 (d, 2H); 7.38 (d, 2H); 7.67 (s, 1H)

[0648] 144. 180 mg of alcohol 150 is treated analogously to 11., and 110mg of[1R-[1α(1R*),3aβ,7aα]]-1-[5-(octahydro-7a-methyl-4-oxo-1H-inden-1-yl]hexyl]-3-[(4-methoxyphenyl)-methoxy]-1H-pyrazole-4-carboxylicacid ethyl ester 151 is obtained as a colorless oil.

[0649]¹H-NMR (CD₂Cl₂) δ=0.62 ppm (s, 3H); 0.97 (d, 3H); 1.28 (t, 3H);3.80 (s, 3H); 3.91 (t, 2H); 4.18 (q, 2H); 5.20 (s, 2H); 6.88 (d, 2H);7.39 (d, 2H); 7.69 (s, 1H)

[0650] 145. 137 mg of phosphine oxide 13, which was deprotonated with0.12 ml of n-butyllithium solution (2.5 M in hexane), is reacted with 60mg of ketone 151 analogously to 12., and 76 mg of(7E)-(1R,3R)-1-[1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-yl]-3-[(4-methoxyphenyl)methoxy]-1H-pyrazole-4-carboxylicacid ester 152 is obtained as a colorless foam.

[0651]¹H-NMR (CD₂Cl₂): δ=0.04 ppm (s, 12H); 0.50 (s, 3H); 0.85 (s, 18H);0.91 (d, 3H); 1.28 (t, 3H); 3.77 (s, 3H); 3.88 (t, 2H); 4.04 (m, 2H);4.18 (q, 2H); 5.17 (s, 2H); 5.79 (d, 1H); 6.14 (d, 1H); 6.88 (d, 2H);7.38 (d, 2H); 7.65 (s, 1H)

[0652] 146. 20 mg of silyl ether 152 is reacted analogously to 14., andafter chromatographic purification with ethyl acetate/hexane on silicagel, 8 mg of title compound 153 is obtained as a colorless foam.

[0653]¹H-NMR (CD₂Cl₂) δ=0.50 ppm (s, 3H); 0.88 (d, 3H); 1.24 (t, 3H);3.73 (s, 3H); 3.88 (t, 2H); 3.98 (m, 1H); 4.02 (m, 1H); 4.18 (q, 2H);5.15 (s, 2H); 5.80 (d, 1H); 6.23 (d, 1H); 6.86 (d, 2H); 7.358 (d, 2H);7.64 (s, 1H)

Example 34

[0654](7E)-(1R,3R)-1-(1,3-Dihydroxy-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-yl)-3-hydroxy-1H-pyrazole-4-carboxylicAcid Ethyl Ester 157

[0655] 147. 110 mg of ketone 151 is introduced into 5 ml of ethanol, 40mg of palladium/carbon is added, and it is hydrogenated until hydrogenis no longer taken up. The catalyst is filtered off, then the organicphase is removed, and the residue is chromatographed with ethylacetate/hexane on silica gel, whereby 90 mg of[1R-[1α(1R*),3aβ,7aα]]-1-[5-octahydro-7a-methyl-4-oxo-1H-inden-1-yl]hexyl]-3-hydroxy-1H-pyrazole-4-carboxylicacid ethyl ester 154 accumulates as a colorless oil.

[0656]¹H-NMR (CD₂Cl₂): δ=0.58 ppm (s, 3H); 0.90 (d, 3H); 1.30 (t, 3H);3.90 (t, 2H); 4.28 (q, 2H); 7.57 (s, 1H)

[0657] 148. 90 mg of alcohol 154 is introduced into 3 ml ofdimethylformamide, 0.06 ml of triethylamine and 0.42 ml oft-butyldimethylsilyl chloride (1 M in hexane) are added, and it isstirred for 2 hours at room temperature. Then, it is diluted with sodiumchloride solution, extracted with ethyl acetate, the organic phase iswashed with sodium chloride solution and dried on sodium sulfate. Thesolvent is removed, and the residue is chromatographed on silica gelwith ethyl acetate/hexane, whereby 111 mg of[1R-[1α(R*),3aβ,7aα]]-1-[5-(octahydro-7a-methyl-4-oxo-1H-inden-1-yl]hexyl]-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1H-pyrazole-4-carboxylicacid-ethyl ester 155 is obtained as a colorless oil.

[0658]¹H-NMR (CD₂Cl₂): δ=0.23 ppm (s, 6H); 0.56 (s, 3H); 0.90 (d, 3H);0.99 (s, 9H); 1.26 (t, 3H); 3.84 (t, 2H); 4.20 (q, 2H); 7.64 (s, 1H)

[0659] 149. 171 mg of phosphine oxide 13, which was deprotonated with0.15 ml of n-butyllithium solution (2.5 M in hexane), is reacted with 77mg of ketone 155 analogously to 12., and 41 mg of(7E)-(1R,3R)-1-[1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-yl)-3-([[1,1-dimethylethyl)dimethylsilyl]oxy]-1H-pyrazole-4-carboxylicacid ethyl ester 156 is obtained as a colorless foam.

[0660]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.29 (s, 6H); 0.53 (s, 3H);0.91 (s, 18H); 0.92 (d, 3H); 1.02 (s, 9H); 1.32 (t, 3H); 3.90 (t, 2H);4.09 (m, 2H); 4.27 (q, 2H); 5.82 (d, 1H); 6.18 (d, 1H); 7.65 (s, 1H)

[0661] 150. 41 mg of silyl ether 156 is reacted analogously to 14., andafter chromatographic purification with ethyl acetate/hexane on silicagel, 19 mg of title compound 157 is obtained as a colorless foam.

[0662]¹H-NMR (CD₂Cl₂/CD₃OD): δ=0.50 ppm (s, 3H); 0.83 (d, 3H); 1.27 (t,3H); 3.83 (t, 2H); 3.92 (m, 1H); 3.99 (m, 1H); 4.23 (q, 2H); 5.82 (d,1H);-6.21 (d, 1H); 7.57 (s, 1H)

Example 35

[0663](7E)-(1R,3R,24aR)-24a-(4-Methylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol164a and(7E)-(1R,3R,24aS)-24a-(4-methylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol164b

[0664] 151. 0.84 ml of 4-bromotoluene is introduced into 18 ml oftetrahydrofuran, and 2.72 ml of n-butyllithium solution (2.5 M inhexane) is added at −78° C. After 30 minutes at this temperature, 500 mgof aldehyde 8 in 3 ml of tetrahydrofuran is added in drops, and it isstirred for 1 more hour. Then, it is quenched with sodium chloridesolution, extracted with ethyl acetate, the organic phase is washed withsodium chloride solution and dried on sodium sulfate. The solvent isremoved, and the residue is chromatographed on silica gel with ethylacetate/hexane, whereby 381 mg of[1R-[1α(1R*),3aβ,4α,7aα]]-α-[4-[octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1H-inden-1-yl]pentyl]-4-methylphenylmethanol158 is obtained as a colorless oil.

[0665]¹H-NMR (CDCl₃): δ=0.56 ppm (q, 6H); 0.89 (d, 3H); 0.91 (s, 3H);0.95 (t, 9H); 2.33 (s, 3H); 4.02 (m, 1H); 4.62 (m, 1H); 7.13 (d, 2H);7.23 (d, 2H)

[0666] 152. 315 mg of alcohol 158 is treated analogously to 9., and 302mg of[1R-[1α(1R*),3aβ,4α,7aα]]-5-[octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1H-inden-1-yl]-1-(4-methylphenyl)hexyl-acetate159 is obtained as a colorless oil.

[0667]¹H-NMR (CDCl₃): δ=0.56 ppm (q, 6H); 0.88/0.89 (d, 3H); 0.90 (s,3H); 0.95 (t, 9H); 2.05 (s, 3H); 2.35 (s, 3H); 4.02 (m, 1H); 5.70 (m,1H); 7.14 (d, 2H); 7.22 (d, 2H)

[0668] 153. 300 mg of acetate 159 is treated analogously to 10., and 228mg of[1R-(1α(1R*),3aβ,4α,7aα]]-1-[5-(acetyloxy)-1-methyl-5-(4-methylphenyl)pentyl]octahydro-7a-methyl-1H-inden-4-ol160 is obtained as a colorless oil.

[0669]¹H-NMR (CDCl₃): δ=0.87/0.88 ppm (d, 3H); 0.90/0.91 (s, 3H); 2.07(s, 3H); 2.35 (s, 3H); 4.08 (m, 1H); 5.70 (m, 1H); 7.15 (d, 2H); 7.22(d, 2H)

[0670] 154. 227 mg of alcohol 160 is treated analogously to 11., and 185mg of[1R-[1α(1R*),3aβ,7aα]]-1-[5-(acetyloxy)-1-methyl-5-(4-methylphenyl)pentyl]octahydro-7a-methyl-4H-inden-4-one161 is obtained as a colorless oil.

[0671]¹H-NMR (CDCl₃): δ=0.62/0.63 ppm (s, 3H); 0.92/0.93 (d, 3H); 2.05(s, 3H); 2.35 (s, 3H); 5.69 (m, 1H); 7.12 (d, 2H); 7.21 (d, 2H)

[0672] 155. 267 mg of phosphine oxide 13, which was deprotonated with0.23 ml of n-butyllithium solution (2.5 M in hexane), is reacted with 90mg of ketone 161 analogously to 12., and 163 mg of(7E)-(1R,3R)-24a-(acetyloxy)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-(4-methylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-diene162 is obtained as a colorless foam.

[0673]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.52/0.53 (s, 3H); 0.90 (s,18H); 0.91 (d, 3H); 2.07 (s, 3H); 2.35 (s, 3H); 4.08 (m, 2H); 5.70 (m,1H); 5.80 (d, 1H); 6.18 (d, 1H); 7.15 (d, 2H); 7.22 (d, 2H)

[0674] 156. 162 mg of acetate 162 is reacted analogously to 13., and 147mg of(7E)-(1R,3R)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl)oxy]-24a-(4-methylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-ol163 is obtained as a colorless foam.

[0675]¹H-NMR (CDCl₃): δ=0.04 ppm (s, 12H); 0.52/0.53 (s, 3H); 0.88 (s,18H); 0.89 (d, 3H); 2.25 (s, 3H); 4.08 (m, 2H); 4.63 (m, 1H); 5.82 (d,1H); 6.18 (d, 1H); 7.17 (d, 2H); 7.25 (d, 2H)

[0676] 157. 115 mg of alcohol 163 is treated analogously to 14., andafter the diastereomers (in terms of C-24a) are separated by HPLC, 27 mgof title compound 164a and 30 mg of title compound 164b are obtained ascolorless foams.

[0677]¹H-NMR (CD₂Cl₂/CD₃OD): 164a: δ=0.48 ppm (s, 3H); 0.86 (d, 3H);2.28 (s, 3H); 3.91 (m, 1H); 3.98 (m, 1H); 4.51 (t, 1H); 5.80 (d, 1H);6.21 (d, 1H); 7.10 (d, 2H); 7.17 (d, 2H)

[0678] 164b: δ=0.49 ppm (s, 3H); 0.86 (d, 3H); 2.28 (s, 3H); 3.91-(m,1H); 3.98 (m, 1H); 4.52 (t, 1H); 5.80 (d, 1H); 6.22 (d, 1H); 7.10 (d,2H); 7.17 (d, 2H)

Example 36

[0679](7E)-(1R,3R)-1,3-Dihydroxy-24a-(4-methylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one166

[0680] 158. 31 mg of alcohol 163 is treated analogously to 25., whereby19 mg of(7E)-(1R,3R)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]-oxy]-24a-(4-methylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one165 accumulates as a colorless foam.

[0681]¹H-NMR (CD₂Cl₂): δ=0.04 ppm (s, 12H); 0.52 (s, 3H); 0.86 (s, 18H);0.93 (d, 3H); 2.38 (s, 3H); 4.06 (m, 2H); 5.80 (d, 1H); 6.15 (d, 1H);7.22 (d, 2H); 7.80 (d, 2H)

[0682] 159. 18 mg of ketone 165 is treated analogously to 26., whereby 9mg of title compound 166 accumulates as a colorless foam.

[0683]¹H-NMR (CD₂Cl₂): δ=0.53 ppm (s, 3H); 0.95 (d, 3H); 2.38 (s, 3H);3.96 (m, 1H); 4.03 (m, 1H); 5.84 (d, 1H); 6.26 (d, 1H); 7.26 (d, 2H);7.84-(d, 2H)

Example 37

[0684](7E)-(1R,2R,3R,24aR)-24a-(4-Methylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,2,3,24a-tetrol169a and(7E)-(1R,2S,3R,24aS)-24a-(4-methylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,2,3,24a-tetrol169b

[0685] 160. 327 mg of[2-[(3S-(3R,4S,5R)]-3,4,5-tris[[(1,1-dimethylethyl)dimethylsilyl]oxy]cyclo-hexylidene]ethyl]diphenylphosphineoxide 61b [H. F. DeLuca et al. J. Med. Chem. 37, 3730 (1994)], which wasdeprotonated with 0.22 ml of n-butyllithium solution, is reacted with 90mg of ketone 161 analogously to 58., and 118 mg of(7E)-(1R,2R,3R)-24a-(acetyloxy)-1,2,3-tris[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-(4-methylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-diene167 is obtained as a colorless foam.

[0686]¹H-NMR (CDCl₃): δ=0.03-0.08 ppm (4×s, 18H); 0.52 (s, 3H); 0.86 (s,9H); 0.90 (s, 18H); 0.91 (d, 3H); 2.07 (s, 3H); 2.35 (s, 3H); 3.65 (m,1H); 3.85 (m, 1H); 3.96 (m, 1H); 5.69 (m, 1H); 5.80 (d, 1H); 6.18 (d,1H); 7.15 (d, 2H); 7.22 (d, 2H)

[0687] 161. 117 mg of(7E)-(1R,2R,3R)-1,2,3-tris[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-(4-methylphenyl)-24a-homo-19-nor-9′,10-secochola-5,7-dien-24a-ol167 is reacted analogously to 13., and 109 mg of 168 is obtained as acolorless foam.

[0688]¹H-NMR (CDCl₃): δ=0.03-0.08 ppm (4×s, 18H); 0.52 (s, 3H); 0.85 (s,9H); 0.90 (s, 18H); 0.91 (d, 3H); 2.35 (s, 3H); 3.65 (m, 1H); 3.84 (m,1H); 3.95 (m, 1H); 4.63 (m, 1H); 5.80 (d, 1H); 6.17 (d, 1H); 7.18 (d,2H); 7.24 (d, 2H)

[0689] 162. 108 mg of alcohol 168 is treated analogously to 14., andafter the diastereomers (in terms of C-24a) are separated by HPLC, 12 mgof title compound 169a and 16 mg of title compound 169b are obtained ascolorless foams.

[0690]¹H-NMR (CD₂Cl₂): 169a: δ=0.51 ppm (s, 3H); 0.89 (d, 3H); 2.29 (s,3H); 3.45 (m, 1H); 3.60 (m, 1H); 4.00 (m, 1H); 4.59 (m, 1H); 5.81 (d,1H); 6.22 (d, 1H); 7.11 (d, 2H); 7.20 (d, 2H)

[0691] 169b: δ=0.50 ppm (s, 3H); 0.88 (d, 3H); 2.29 (s, 3H); 3.45 (m,1H); 3.60 (m, 1H); 4.00 (m, 1H); 4.60 (t, 1H); 5.81 (d, 1H); 6.22 (d,1H); 7.11 (d, 2H); 7.20 (d, 2H)

Example 38

[0692](7E)-(1R,3R,24aR)-24a-(4-Trifluoromethylphenyl)-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol176a and(7E)-(1R,3R,24aS)-24a-(4-trifluoromethylphenyl)-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol176b

[0693] 163. 1.39 ml of 4-trifluoromethylbromobenzene is introduced into20 ml of tetrahydrofuran, and 3.96 ml of n-butyllithium solution (2.5 Min hexane) is added at −78° C. After 30 minutes at this temperature, 762mg of aldehyde 8 in 5 ml of tetrahydrofuran is added in drops, and it isstirred for 1 more hour. Then, it is quenched with sodium chloridesolution, extracted with ethyl acetate, the organic phase is washed withsodium chloride solution and dried on sodium sulfate. The solvent isremoved, and the residue is chromatographed on silica gel with ethylacetate/hexane, whereby 587 mg of[1R-[1α(1R*),3aβ,4α,7aα]]-α-[4-[octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1H-inden-1-yl]pentyl]-4-(trifluoromethylphenyl)methanol170 is obtained as a colorless oil.

[0694]¹H-NMR (CDCl₃): δ=0.56 ppm (q, 6H); 0.89 (d, 3H); 0.91 (s, 3H);0.95 (t, 9H); 2.33 (s, 3H); 4.02 (m, 1H); 4.75 (m, 1H); 7.48 (d, 2H);7.61 (d, 2H)

[0695] 164. 580 mg of alcohol 170 is treated analogously to 9., and 566mg of[1R-[1α(1R*),3aβ,4α,7aα]]-5-[octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1H-inden-1-yl]-1-(4-trifluoromethylphenyl)hexyl-acetate171 is obtained as a colorless oil.

[0696]¹H-NMR (CDCl₃): δ=0.56 ppm (q, 6H); 0.88/0.89 (d, 3H); 0.90/0.91(s, 3H); 0.95-(t, 9H); 2.10 (s, 3H); 4.02 (m, 1H); 5.74 (m, 1H); 7.42(d, 2H); 7.61 (d, 2H)

[0697] 165. 556 mg of acetate 171 is treated analogously to 10., and 208mg of[1R-[1α(1R*),3aβ,4α,7aα]]-1-[5-(acetyloxy)-1-methyl-5-(4-trifluoromethylphenyl)pentyl]octahydro-7a-methyl-1H-inden-4-ol172 is obtained as a colorless oil.

[0698]¹H-NMR (CDCl₃): δ=0.88/0.89 ppm (d, 3H); 0.91/0.92 (s, 3H); 2.11(s, 3H); 4.08 (m, 1H); 5.75 (m, 1H); 7.43 (d, 2H); 7.61 (d, 2H)

[0699] 166. 160 mg of alcohol 172 is treated analogously to 11., and 138mg of[1R-[1α(1R*),3aβ,7aα]]-1-[5-(acetyloxy)-1-methyl-5-(4-trifluoromethylphenyl)pentyl]octahydro-7a-methyl-4H-inden-4-one173 is obtained as a colorless oil.

[0700]¹H-NMR (CDCl₃): δ=0.61/0.62 ppm (s, 3H); 0.92/0.93 (d, 3H); 2.09(s, 3H); 5.75 (m, 1H); 7.45 (d, 2H); 7.61 (d, 2H)

[0701] 167. 348 mg of phosphine oxide 13, which was deprotonated with0.29 ml of n-butyllithium solution (2.5 M in hexane), is reacted with134 mg of ketone 173 analogously to 12., and 173 mg of(7E)-(1R,3R)-24a-(acetyloxy)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-(4-trifluoromethyl-phenyl)-24a-homo-19-nor-9,10-secochola-5,7-diene174 is obtained as a colorless foam.

[0702]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.52/0.53 (s, 3H); 0.90 (s,18H); 0.91 (d, 3H); 2.10)(s, 3H); 4.08 (m, 2H); 5.73 (m, 1H); 5.80 (d,1H); 6.18 (d, 1H); 7.44 (d, 2H); 7.61 (d, 2H)

[0703] 168. 173 mg of acetate 174 is treated analogously to 13., and 147mg of(7E)-(1R,3R)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-(4-trifluoromethylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-ol175 is obtained as a colorless foam.

[0704]¹H-NMR (CDCl₃): δ=0.05 ppm (s, 12H); 0.52/0.53 (s, 3H); 0.89 (s,18H); 0.90 (d, 3H); 4.09 (m, 2H); 4.76 (m, 1H); 5.81 (d, 1H); 6.18 (d,1H); 7.48 (d, 2H); 7.61 (s, 2H)

[0705] 169. 113 mg of alcohol 175 is treated analogously to 14., andafter the diastereomers (in terms of C-24a) are separated by HPLC, 21 mgof title compound 176a and 19 mg of title compound 176b are obtained ascolorless foams.

[0706]¹H-NMR (CD₂Cl₂): 176a: δ=0.51 ppm (s, 3H); 0.86 (d, 3H); 3.95 (m,1H); 4.02 (m, 1H); 4.73 (t, 1H); 5.82 (d, 1H); 6.25 (d, 1H); 7.45 (d,2H); 7.60 (d, 2H)

[0707] 176b: δ=0.51 ppm (s, 3H); 0.86 (d, 3H); 3.95 (m, 1H); 4.02 (m,1H); 4.74 (t, 1H); 5.82 (d, 1H); 6.25 (d, 1H); 7.45 (d, 2H); 7.60 (d,2H)

Example 39

[0708](7E)-(1R,3R)-1,3-Dihydroxy-24a-(4-trifluoromethylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one178

[0709] 170. 33 mg of alcohol 175 is treated analogously to 25., whereby18 mg of(7E)-(1R,3R)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-(4-trifluoromethylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one177 accumulates as a colorless foam.

[0710]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.54 (s, 3H); 0.89 (s, 18H);0.98 (d, 3H); 4.08 (m, 2H); 5.82 (d, 1H); 6.18 (d, 1H); 7.73 (d, 2H);8.08 (d, 2H)

[0711] 171. 18 mg of ketone 177 is treated analogously to 26., whereby 9mg of title compound 178 accumulates as a colorless foam.

[0712]¹H-NMR (CD₂Cl₂): δ=0.54 ppm (s, 3H); 0.95 (d, 3H); 3.96 (m, 1H);4.03 (m, 1H); 5.85 (d, 1H); 6.26 (d, 1H); 7.73 (d, 2H); 8.05 (d, 2H)

Example 40

[0713](7E)-(1R,3R,24aR)-24a-(4-Methoxyphenyl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol185a and(7E)-(1R,3R,24aS)-24a-(4-methoxyphenyl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol185b

[0714] 172. 0.85 ml of 4-bromoanisole is introduced into 18 ml oftetrahydrofuran, and 2.72 ml of n-butyllithium solution (2.5 M inhexane) is added at −78° C. After 30 minutes at this temperature, 500 mgof aldehyde 8 in 4 ml of tetrahydrofuran is added in drops, and it isstirred for 1 more hour. Then, it is quenched with sodium chloridesolution, extracted with ethyl acetate, the organic phase is washed withsodium chloride solution and dried on sodium sulfate. The solvent isremoved, and the residue is chromatographed on silica gel with ethylacetate/hexane, whereby 497 mg of[1R-[1α(1R*),3aβ,4α,7aα]]-α-[4-[octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1H-inden-1-yl]pentyl]-4-(methoxyphenyl)methanol179 is obtained as a colorless oil.

[0715]¹H-NMR (CDCl₃): δ=0.54 ppm (q, 6H); 0.89 (d, 3H); 0.90 (s, 3H);0.94 (t, 9H); 3.80 (s, 3H); 4.01 (m, 1H); 4.61 (m, 1H); 6.88 (d, 2H);7.28 (d, 2H)

[0716] 173. 490 mg of alcohol 179 is treated analogously to 9., and 509mg of[1R-[1α(1R*),3aβ,4α,7aα]]-5-[octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1H-inden-1-yl]-1-(4-methoxyphenyl)hexyl-acetate180 is obtained as a colorless oil.

[0717]¹H-NMR (CDCl₃): δ=0.56 ppm (q, 6H); 0.88/0.89 (d, 3H); 0.90/0.91(s, 3H); 0.95 (t, 9H); 2.06 (s, 3H); 3.80 (s, 3H); 4.02 (m, 1H); 5.69(m, 1H); 6.88 (d, 2H); 7.28 (d, 2H)

[0718] 174. 504 mg of acetate 180 is treated analogously to 10., and 280mg of[1R-[1α(1R*),3aβ,4α,7aα]]-1-[5-(acetyloxy)-1-methyl-5-(4-methoxyphenyl)pentyl]octahydro-7a-methyl-1H-inden-4-ol181 is obtained as a colorless oil.

[0719]¹H-NMR (CDCl₃): δ=0.87/0.88 ppm (d, 3H); 0.91/0.92 (s, 3H); 2.07(s, 3H); 3.80 (s, 3H); 4.08 (m, 1H); 5.68 (m, 1H); 6.88 (d, 2H); 7.28(d, 2H)

[0720] 175. 275 mg of alcohol 181 is treated analogously to 11., and 252mg of[1R-[1α(1R*),3aβ,7aα]]-1-[5-(acetyloxy)-1-methyl-5-(4-methoxyphenyl)pentyl]octahydro-7a-methyl-4H-inden-4-one182 is obtained as a colorless oil.

[0721]¹H-NMR (CDCl₃): δ=0.61/0.62 ppm (s, 3H); 0.91/0.92 (d, 3H); 2.07(s, 3H); 3.80 (s, 3H); 5.68 (m, 1H); 6.88 (d, 2H); 7.28 (d, 2H)

[0722] 176. 370 mg of phosphine oxide 13, which was deprotonated with0.30 ml of n-butyllithium solution (2.5 M in hexane), is reacted with130 mg of ketone 182 analogously to 12., and 206 mg of(7E)-(1R,3R)-24a-(acetyloxy)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-(4-methoxyphenyl)-24a-homo-19-nor-9,10-secochola-5,7-diene183 is obtained as a colorless foam.

[0723]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.52/0.53 (s, 3H); 0.90 (s,18H); 0.91 (d, 3H); 2.03 (s, 3H); 3.81 (s, 3H); 4.08 (m, 2H); 5.69 (m,1H); 5.81 (d, 1H); 6.18 (d, 1H); 6.88 (d, 2H); 7.28 (d, 2H)

[0724] 177. 200 mg of acetate 183 is reacted analogously to 13., and 175mg of(7E)-(1R,3R)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-(4-methoxyphenyl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-ol184 is obtained as a colorless foam.

[0725]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.52/0.53 (s, 3H); 0.89 (s,18H); 0.90 (d, 3H); 3.80 (s, 3H); 4.09 (m, 2H); 4.63 (m, 1H); 5.81 (d,1H); 6.18 (d, 1H); 6.90 (d, 2H); 7.30 (d, 2H)

[0726] 178. 130 mg of alcohol 184 is treated analogously to 14., andafter diastereomers (in terms of C-24a) are separated by HPLC, 26 mg oftitle compound 185a and 22 mg of title compound 185b are obtained ascolorless foams.

[0727]¹H-NMR (CD₂Cl₂): 185a: δ=0.52 μm (s, 3H); 0.89 (d, 3H); 3.80 (s,3H); 3.97 (m, 1H); 4.04 (m, 1H); 4.59 (t, 1H); 5.82 (d, 1H); 6.27 (d,1H); 6.88 (d, 2H); 7.25 (d, 2H)

[0728] 185b: δ=0.52 ppm (s, 3H); 0.89 (d, 3H); 3.79 (s, 3H); 3.97 (m,1H); 4.04 (m, 1H); 4.60 (t, 1H); 5.82 (d, 1H); 6.27 (d, 1H); 6.88 (d,2H); 7.25 (d, 2H)

Example 41

[0729](7E)-(1R,3R)-1,3-Dihydroxy-24a-(4-methoxyphenyl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one187

[0730] 179. 44 mg of alcohol 184 is treated analogously to 25., whereby27 mg of(7E)-(1R,3R)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-(4-methoxyphenyl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one186 accumulates as a colorless foam.

[0731]¹H-NMR (CD₂Cl₂): δ=0.04 ppm (s, 12H); 0.51 (s, 3H); 0.84 (s, 18H);0.94 (d, 3H); 3.82 (s, 3H); 4.08 (m, 2H); 5.81 (d, 1H); 6.15 (d, 1H);6.91 (d, 2H); 7.90 (d, 2H)

[0732] 180. 27 mg of ketone 186 is treated analogously to 26., whereby16 mg of title compound 187 accumulates as a colorless foam.

[0733]¹H-NMR (CD₂Cl₂): δ=0.51 ppm (s, 3H); 0.92 (d, 3H); 3.80 (s, 3H);3.96 (m, 1H); 4.02 (m, 1H); 5.83 (d, 1H); 6.24 (d, 1H); 6.92 (d, 2H);7.91 (d, 2H)

Example 42

[0734](7E)-(1R,3R,20S,24aR)-24a-(Thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol202a and(7E)-(1R,3R,20S,24aS)-24a-(thiazol-2-yl)-24-a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol202b

[0735] 181. 3.89 g of alcohol 3 is introduced into 250 ml ofdichloromethane, and 7.74 g of pyridinium chlorochromate is added. It isstirred for 3 hours at room temperature and then diluted with diethylether, suctioned off on Celite and concentrated by evaporation. Theresidue is chromatographed on silica gel with ethyl acetate/hexane,whereby 3.19 g of[1R[1α(1S*),3aβ,4α,7aα]]-2-[octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1H-inden-1-yl]propanol188 is obtained as a colorless oil.

[0736]¹H-NMR (CDCl₃): δ=0.56 ppm (q, 6H); 0.93 (s, 3H); 0.94 (t, 9H);1.10 (t, 9H); 4.07 (m, 1H); 9.58 (s, 1H)

[0737] 182. 6.23 g of aldehyde 188 is introduced into 60 ml of tolueneand 60 ml of methanol, 4 ml of diazabicycloundecane is added, and it isstirred for 4 days at room temperature. The crude product isconcentrated by evaporation and chromatographed on silica gel with ethylacetate/hexane, whereby 5.63 g of the diastereomer mixture[1R-[1α(1S*),3aβ,4α,7aα]]-2-[octahydro-7a-methyl-4-[(triethylsilyl)-oxy]-1H-inden-1-yl]propanal188 and[1R[1α(1R*),3aβ,4α,7aα]]-2-[octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1H-inden-1-yl]propanal189 are obtained as a colorless oil.

[0738]¹H-NMR (CDCl₃): 189: δ=0.56 ppm (q, 6H); 0.93 (d, 3H); 0.94 (t,9H); 1.02 (d, 3H); 4.07 (m, 1H); 9.53 (d, 1H)

[0739] 183. 5.63 g of the epimer mixture of aldehyde 188/189 isdissolved in 100 ml of ethanol and 10 ml of tetrahydrofuran, and 377 mgof sodium borohydride is added in portions. It is stirred for 1 hour atroom temperature and then carefully quenched with ammonium chloridesolution. It is extracted with dichloromethane, the organic phase iswashed with sodium chloride solution, dried on sodium sulfate andconcentrated by evaporation. The residue is chromatographed on silicagel with ethyl acetate/hexane, whereby 2.61 g of[1R[1α(1R*),3aβ,4α,7aα]]-2-[octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1H-inden-1-yl]-1-propanol190 in addition to 2.10 g of compound 3 that is normally configured at20 are obtained as colorless oils.

[0740]¹H-NMR (CDCl₃): δ=0.55 ppm (q, 6H); 0.92 (d, 3H); 0.94 (t, 9H);0.98 (d, 3H); 3.46 (dd, 1H); 3.72 (dd, 1H); 4.03 (m, 1H)

[0741] 184. 2.61 g of alcohol 190 is introduced into 80 ml of pyridine,cooled to 0° C., and 3.04 g of p-toluenesulfonyl chloride is added. Itis stirred for 5 more hours at this temperature, and then the reactionmixture is poured onto sodium bicarbonate solution. It is extracted withethyl acetate, the organic phase is washed with sodium chloride solutionand dried on sodium sulfate. The residue is chromatographed on silicagel with ethyl acetate/hexane, whereby 3.19 g of[1R-[1α(1R*),3aβ,4α,7aα]]-2-[octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1H-inden-1-yl]propyl-(4-methylbenzenesulfonate)191 is obtained as a colorless oil.

[0742]¹H-NMR (CDCl₃): δ=0.54 ppm (q, 6H); 0.81 (s, 3H); 0.88 (d, 3H);0.94 (t, 9H); 2.47 (s, 3H); 3.78 (dd, 1H); 4.01 (m, 1H); 4.12 (dd, 1H);7.34 (d, 1H); 7.79 (d, 1H)

[0743] 185. 4.5 ml of propargyl-THP-ether is introduced into 100 ml ofdioxane, and 12.8 ml of n-butyllithium solution (2.5 M in hexane) isadded in drops. After 1 hour, 3.18 g of tosylate 191 in 20 ml of dioxaneis added in drops. For 2 days, it is now heated to boiling. Aftercooling, it is quenched with sodium bicarbonate solution, extracted withethyl acetate, the organic phase is washed with sodium chloride solutionand concentrated by evaporation. The residue is chromatographed onsilica gel with ethyl acetate/hexane, whereby 2.62 g of[1R[1α(1S*),3aβ,4α,7aα]]-octahydro-7a-methyl-1-[5-[(tetrahydro-2H-pyran-2-yl)oxy]-1-methyl-3-pentinyl]-4-[(triethylsilyl)oxy]-1H-indene192 is obtained as a colorless oil.

[0744]¹H-NMR (CDCl₃): δ=0.55 ppm (q, 6H); 0.89 (s, 3H); 0.92 (d, 3H);0.94 (t, 9H); 4.02 (m, 1H); 4.28 (m, 2H); 4.94 (m, 1H)

[0745] 186. 2.62 g of alkine 192 is introduced into 50 ml of ethylacetate, 465 mg of palladium/carbon (10%) and 1.06 g of sodiumbicarbonate are added and hydrogenated at normal pressure. The reactionmixture is then filtered on Celite and concentrated by evaporation. Thecrude product (2.08 g) of[1R[1α(1S*),3aβ,4α,7aα]]-octahydro-7a-methyl-1-[5-[(tetrahydro-2H-pyran-2-yl)oxy]-1-methyl-pentyl]-4-[(triethylsilyl)oxy]-1H-indene193 is immediately further reacted.

[0746] 187. 2.08 g of THP-ether 193 is introduced into 100 ml ofdichloromethane, and 9.2 ml of diethylaluminum chloride solution (1.8 Min toluene) is added in drops. After 2 hours at room temperature, it isquenched with isopropanol/water (15:85), toluene is added, and stirringis continued overnight. Then, it is suctioned off on Celite andconcentrated by evaporation. The residue is chromatographed on silicagel with ethyl acetate/hexane, whereby 1.02 g of[1R-[1α(1S*),3aβ,4α,7aα]]-5-[octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1H-inden-1-yl]-1-hexanol194 is obtained as a colorless oil.

[0747]¹H-NMR (CDCl₃): δ=0.56 ppm (q, 6H); 0.82 (d, 3H); 0.92 (s, 3H);0.96 (t, 9H); 3.64 (t, 2H); 4.02 (m, 1H)

[0748] 188. 1.02 g of alcohol 194 is dissolved in 40 ml ofdichloromethane, and then 835 mg of pyridinium chlorochromate is added.It is stirred for 2 hours at room temperature, then diethyl ether isadded, filtered on Celite and concentrated by evaporation. The residueis chromatographed on silica gel with ethyl acetate/hexane, whereby 810mg of[1R[1α(1S*),3aβ,4α,7aα]]-5-[octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1H-inden-1-yl]hexanal195 is obtained as a colorless oil.

[0749]¹H-NMR (CDCl₃): δ=0.56 ppm (q, 6H); 0.83 (d, 3H); 0.91 (s, 3H);0.96 (t, 9H); 2.40 (t, 2H); 4.02 (m, 1H); 9.78 (sbr, 1H)

[0750] 189. 0.99 ml of 2-bromothiazole is introduced into 20 ml oftetrahydrofuran, and 4.42 ml of n-butyllithium solution (2.5 M inhexane) is added at −78° C. After 30 minutes at this temperature, 810 mgof aldehyde 195 in 5 ml of tetrahydrofuran is added in drops, and it isstirred for 1 more hour. Then, it is quenched with sodium chloridesolution, extracted with ethyl acetate, the organic phase is washed withsodium chloride solution and dried on sodium sulfate. The solvent isremoved, and the residue is chromatographed on silica gel with ethylacetate/hexane, whereby 878 mg of[1R-[1α(1S*),3aβ,4α,7aα]]-α-[4-[octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1H-inden-1-yl]pentyl]thiazole-2-methanol196 is obtained as a colorless oil.

[0751]¹H-NMR (CDCl₃): δ=0.57 ppm (q, 6H); 0.80 (d, 3H); 0.90 (s, 3H);0.97 (t, 9H); 4.02 (m, 1H); 5.01 (m, 1H); 7.30 (d, 1H); 7.72 (d, 1H)

[0752] 190. 878 mg of alcohol 196 is treated analogously to 9., and 709mg of[1R-[1α(1S*),3aβ,4α,7aα]]-5-[octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1H-inden-1-yl]-1-(thiazol-2-yl)hexyl-acetate197 is obtained as a colorless oil.

[0753]¹H-NMR (CDCl₃): δ=0.56 ppm (q, 6H); 0.78/0.79 (d, 3H); 0.89 (s,3H); 0.96 (t, 9H); 2.14 (s, 3H); 4.02 (m, 1H); 6.10 (t, 1H); 7.30 (d,1H); 7.78 (d, 1H)

[0754] 191. 704 mg of acetate 197 is treated analogously to 10., and 490mg of[1R-[1α(1S*),3aβ,4α,7aα]]-1-[5-(acetyloxy)-1-methyl-5-(thiazol-2-yl)pentyl]octahydro-7a-methyl-1H-inden-4-ol198 is obtained as a colorless oil.

[0755]¹H-NMR (CDCl₃): δ=0.78/0.79 ppm (d, 3H); 0.92 (s, 3H); 2.16 (s,3H); 4.07 (m, 1H); 6.10 (t, 1H); 7.30 (d, 1H); 7.78 (d, 1H)

[0756] 192. 485 mg of alcohol 198 is treated analogously to 11., and 480mg of[1R-[1α(1S*),3aβ,7aα]]-α-[5-(acetyloxy)-1-methyl-5-(thiazol-2-yl)pentyl]octahydro-7a-methyl-4H-inden-4-one199 is obtained as a colorless oil.

[0757]¹H-NMR (CDCl₃): δ=0.60 ppm (s, 3H); 0.81/0.82 (d, 3H); 2.13 (s,3H); 6.10 (t, 1H); 7.31 (d, 1H); 7.78 (d, 1H)

[0758] 193. 665 mg of phosphine oxide 13, which was deprotonated with0.56 ml of n-butyllithium solution (2.5 M in hexane), is reacted with220 mg of ketone 199 analogously to 12., and 299 mg of(7E)-(1R,3R,20S)-2-4a-(acetyloxy)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene200 is obtained as a colorless foam.

[0759]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.53 (s, 3H); 0.83 (d, 3H);0.89 (s, 18H); 2.18 (s, 3H); 4.08 (m, 2H); 5.82 (d, 1H); 6.10 (t, 1H);6.18 (d, 1H); 7.31 (d, 1H); 7.78 (d, 1H)

[0760] 194. 299 mg of acetate 200 is reacted analogously to 13., and 240mg of(7E)-(1R,3R,20S)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-ol201 is obtained as a colorless foam.

[0761]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.53 (s, 3H); 0.83 (d, 3H);0.89 (s, 18H); 4.07 (m, 2H); 5.01 (m, 1H); 5.81 (d, 1H); 6.18 (d, 1H);7.30 (d, 1H); 7.72 (d, 1H)

[0762] 195. 192 mg of alcohol 201 is treated analogously to 14., andafter the diastereomers (in terms of C-24a) are separated by HPLC, 41 mgof title compound 202a and 49 mg of title compound 202b are obtained ascolorless foams.

[0763]¹H-NMR (CD₂Cl₂/CD₃OD): 202a: δ=0.50 ppm (s, 3H); 0.80 (d, 3H);3.93 (m, 1H); 4.01 (m, 1H); 4.90 (t, 1H); 5.82 (d, 1H); 6.24 (d, 1H);7.29 (d, 1H); 7.68 (d, 1H)

[0764] 202b: δ=0.50 ppm (s, 3H); 0.80 (d, 3H); 3.93 (m, 1H); 4.01 (m,1H); 4.91 (t, 1H); 5.82 (d, 1H); 6.24 (d, 1H); 7.30 (d, 1H); 7.68 (d,1H)

Example 43

[0765](7E)-(1R,3R,20S)-1,3-Dihydroxy-24a-(thiazol-2-yl)-24-a-homo-19-nor-9,10-secochola-5,7-dien-24a-one204

[0766] 196. 43 mg of alcohol 201 is treated analogously to 25., whereby32 mg of(7E)-(1R,3R,20S)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one203 accumulates as a colorless foam.

[0767]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.52 (s, 3H); 0.88 (s, 18H);0.89 (d, 3H); 4.08 (m, 2H); 5.81 (d, 1H); 6.18 (d, 1H); 7.68 (d, 1H);8.00 (d, 12H)

[0768] 197. 31 mg of ketone 203 is treated analogously to 26., whereby12 mg of title compound 204 accumulates as a colorless foam.

[0769]¹H-NMR (CD₂Cl₂): δ=0.51 ppm (s, 3H); 0.88 (d, 3H); 3.97 (m, 1H);4.03 (m, 1H); 5.82 (d, 1H); 6.26 (d, 1H); 7.67 (d, 1H); 7.97 (d, 1H)

Example 44

[0770](5Z,7E)-(1S,3R,20S,24aR)-24a-(Thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol205a and(5Z,7E)-(1S,3R,20S,24aS)-24a-(thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol205b

[0771] 198. 740 mg of phosphine oxide 17, which was deprotonated with0.61 ml of n-butyllithium solution (2.5 M in hexane), is reacted with240 mg of ketone 199 analogously to 15., and 392 mg of(5Z,7E)-(1S,3R,20S)-24a-(acetyloxy)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-(thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene205 is obtained as a colorless foam.

[0772]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.52 (s, 3H); 0.83 (d, 3H);0.90 (s, 18H); 2.16 (s, 3H); 4.19 (m, 1H); 4.38 (m, 1H); 4.88 (s, 1H);5.19 (s, 1H); 6.01 (d, 1H); 6.10 (t, 1H); 6.24 (d, 1H); 7.31 (d, 1H);7.78 (d, 1H)

[0773] 199. 392 mg of acetate 205 is reacted analogously to 13., and 274mg of(5Z,7E)-(1S,3R,20S)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-(thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-ol206 is obtained as a colorless foam.

[0774]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.52 (s, 3H); 0.83 (d, 3H):0.90 (s, 18H); 4.19 (m, 1H); 4.38 (m, 1H); 4.88 (s, 1H); 5.01 (m, 1H);5.18 (s, 1H); 6.01 (d, 1H); 6.23 (d, 1H); 7.30 (d, 1H); 7.72 (d, 1H)

[0775] 200. 218 mg of alcohol 206 is treated analogously to 14., andafter the diastereomers (in terms of C-24a) are separated by HPLC, 40 mgof title compound 207a and 39 mg of title compound 207b are obtained ascolorless foams.

[0776]¹H-NMR (CD₂Cl₂/CD₃OD): 207a: δ=0.50 ppm (s, 3H); 0.79 (d, 3H);4.13 (m, 1H); 4.34 (m, 1H); 4.90 (t, 1H); 4.93 (s, 1H); 5.28 (s, 1H);6.00 (d, 1H); 6.32 (d, 1H); 7.30 (d, 1H); 7.69 (d, 1H)

[0777] 207b: δ=0.50 ppm (s, 3H); 0.80 (d, 3H); 4.13 (m, 1H); 4.34 (m,1H); 4.91 (t, 1H); 4.93 (s, 1H); 5.28 (s, 1H); 6.00 (d, 1H); 6.32 (d,1H); 7.30 (d, 1H); 7.69 (d, 1H)

Example 45

[0778](5Z,7E)-(1S,3R,20S)-1,3-Dihydroxy-24a-(thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one209

[0779] 201. 51 mg of alcohol 206 is treated analogously to 25., whereby42 mg of(5Z,7E)-(1S,3R,20S)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-(thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one208 accumulates as a colorless foam.

[0780]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.52 (s, 3H); 0.89 (s, 18H);0.90 (d, 3H); 4.19 (m, 1H); 4.38 (m, 1H); 4.88 (s, 1H); 5.19 (s, 1H);6.02 (d, 1H); 6.24 (d, 1H); 7.68 (d, 1H); 8.00 (d, 1H)

[0781] 202. 41 mg of ketone 208 is treated analogously to 26., whereby14 mg of title compound 209 accumulates as a colorless foam.

[0782]¹H-NMR (CD₂Cl₂): δ=0.50 ppm (s, 3H); 0.86 (d, 3H); 4.15 (m, 1H);4.36 (m, 1H); 4.94 (s, 1H); 5.28 (s, 1H); 6.00 (d, 1H); 6.34 (d, 1H);7.66 (d, 1H); 7.96 (d, 1H)

Example 46

[0783](5Z,7E)-(1S,3R,24S)-24-(Thiazol-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol217a and(5Z,7E)-(1S,3R,24R)-24-(thiazol-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol217b

[0784] 203. 21 g of(5Z,7E)-(1S,3R,20S)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-20-methyl-9,10-secopregna-5,7,10(19)-trien-21-al210 (Schering A G, WO 97/41096) is dissolved in 70 ml of tetrahydrofuranand 140 ml of ethanol, and 715 mg of sodium borohydride is added at 0°C. It is stirred for 1 hour at 0° C. and then quenched with ammoniumchloride solution. It is extracted with ethyl acetate, the organic phaseis washed with sodium chloride solution, dried on sodium sulfate andconcentrated by evaporation. The residue is chromatographed on silicagel with ethyl acetate/hexane, whereby 20.54 g of 211 is obtained as acolorless foam.

[0785]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.56 (s, 3H); 0.89 (s, 18H);1.08 (d, 3H); 3.40 (dd, 1H); 3.67 (dd, 1H); 4.19 (m, 1H); 4.38 (m, 1H);4.87 (s, 1H); 5.19 (s, 1H); 6.02 (d, 1H); 6.23 (d, 1H)

[0786] 204. 14.54 g of alcohol 211 is dissolved in 233 ml of pyridine,11.14 g of p-toluenesulfonyl chloride is added, and it is stirred for 4hours at room temperature. It is carefully quenched with sodiumbicarbonate solution, extracted with ethyl acetate, the organic phase iswashed with sodium chloride solution and dried on sodium sulfate. Theresidue is chromatographed with ethyl acetate/hexane on silica gel,whereby 14.73 g of(5Z,7E)-(1S,3R,20S)-1,3-bis[[(1,1-dimethyl-ethyl)dimethylsilyl]oxy]-20-methyl-9,10-secopregna-5,7,10(19)-triene-21-(4-methylbenzenesulfonate)212 is obtained as a colorless foam.

[0787]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.51 (s, 3H); 0.89 (s, 18H);1.00 (d, 3H); 2.47 (s, 3H); 3.71 (dd, 1H); 3.99 (dd, 1H); 4.19 (m, 1H);4.38 (m, 1H); 4.87 (s, 1H); 5.19 (s, 1H); 6.00 (d, 1H); 6.22 (d, 1H);7.37 (d, 2H); 7.80 (d, 2H)

[0788] 205. 14.73 g of tosylate 212 is dissolved in 295 ml ofdichloromethane and 295 ml of acetonitrile, 16.9 g of lithium bromideand 700 mg of 1,8-bis(dimethylamino)naphthalene are added, and it isstirred overnight at 60° C. It is then quenched with sodium chloridesolution, extracted with dichloromethane, the organic phase is washedwith sodium chloride solution, dried on sodium sulfate and concentratedby evaporation. The residue is chromatographed with ethyl acetate/hexaneon silica gel, whereby 9.70 g of(5Z,7E)-(1S,3R,20S)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-21-bromo-20-methyl-9,10-secopregna-5,7,10(19)-triene213 is obtained as a colorless foam.

[0789]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.58 (s, 3H); 0.89 (s, 18H);1.11 (d, 3H); 3.38 (dd, 1H); 3.52 (dd, 1H); 4.19 (m, 1H); 4.38 (m, 1H);4.88 (s, 1H); 5.20 (s, 1H); 6.02 (d, 1H); 6.25 (d, 1H)

[0790] 206. Lithium diisopropylamide is produced from 15.5 ml ofdiisopropylamine and. 49 ml of n-butyllithium (2.5 M in hexane) in 150ml of tetrahydrofuran, cooled to −78° C., and 6.34 ml of acetonitrile isadded in drops. After 30 minutes, 7.8 g of bromide 213 in 20 ml oftetrahydrofuran is added. The reaction mixture is now allowed to heat toroom temperature, stirred for 2 more hours and then quenched with sodiumchloride solution. It is extracted with ethyl acetate, the organic phaseis washed with sodium chloride solution, dried on sodium sulfate andconcentrated by evaporation. The residue is chromatographed with ethylacetate/hexane on silica gel, whereby 5.9 g of(5Z,7E)-(1S,3R)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-9,10-secochola-5,7,10(19)-triene-24-nitrile214 is obtained as a colorless foam.

[0791]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.57 (s, 3H); 0.89 (s, 18H);0.97 (d, 3H); 4.19 (m, 1H); 4.38 (m, 1H); 4.88 (s, 1H); 5.19 (s, 1H);6.02 (d, 1H); 6.23 (d, 1H)

[0792] 207. 3.2 g of nitrile 214 is dissolved in 50 ml oftetrahydrofuran and cooled to 0° C. At this temperature, 16.8 ml ofdiisobutyl aluminum hydride (1.2 M in toluene) is added in drops, and itis stirred for 2 more hours. Then, ammonium chloride solution is added,the precipitate is suctioned off and extracted with ethyl acetate. Theorganic phase is washed with sodium chloride solution, dried on sodiumsulfate and concentrated by evaporation. The residue is chromatographedon silica gel with ethyl acetate/hexane, whereby 2.5 g of(5Z,7E)-(1S,3R)-1,3-bis[[(1,1-dimethylethyl)dimethyl-silyl]oxy]-9,10-secochola-5,7,10(19)-trien-24-al215 is obtained as a colorless foam.

[0793]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.54 (s, 3H); 0.89 (s, 18H);0.94 (d, 3H); 4.19 (m, 1H); 4.38 (m, 1H); 4.88 (s, 1H); 5.19 (s, 1H);6.01 (d, 1H); 6.23 (d, 1H); 9.79 (sbr, 1H)

[0794] 208. 285 mg of thiazole is introduced into 5 ml oftetrahydrofuran, and 1.34 ml of n-butyllithium solution (2.5 M inhexane) is added at −78° C. After 30 minutes at this temperature, 400 mgof aldehyde. 215 in 2 ml of tetrahydrofuran is added, and it is stirredfor 1 more hour. Then, it is quenched with sodium chloride solution,extracted with ethyl acetate, the organic phase is washed with sodiumchloride solution and dried on sodium sulfate. The solvent is removed,and the residue is chromatographed on silica gel with ethylacetate/hexane, whereby 311 mg of(5Z,7E)-(1S,3R)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24-(thiazol-2-yl)-9,10-secochola-5,7,10(19)-trien-24-ol216 is obtained as a colorless oil.

[0795]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.53 (s, 3H); 0.89 (s, 18H);0.95 (d, 3H); 4.19 (m, 1H); 4.38 (m, 1H); 4.88 (s, 1H); 4.98 (m, 1H);5.19 (s, 1H); 6.01 (d, 1H); 6.23 (d, 1H); 7.30 (d, 1H); 7.72 (d, 1H)

[0796] 209. 130 mg of alcohol 216 is treated analogously to 14., andafter the diastereomers (in terms of C-24a) are separated by HPLC, 19 mgof title compound 217a and 16 mg of title compound 217b are obtained ascolorless foams.

[0797]¹H-NMR (CD₂Cl₂/CD₃OD): 217a: δ=0.50 ppm (s, 3H); 0.92 (d, 3H);4.10 (m, 1H); 4.33 (m, 1H); 4.85 (m, 1H); 4.93 (s, 1H); 5.28 (s, 1H);6.01 (d, 1H); 6.32 (d, 1H); 7.32 (d, 1H); 7.64 (d, 1H)

[0798] 217b: δ=0.51 ppm (s, 3H); 0.92 (d, 3H); 4.10 (m, 1H); 4.33 (m,1H); 4.86 (m, 1H); 4.93 (s, 1H); 5.28 (s, 1H); 6.01 (d, 1H); 6.33 (d,1H); 7.32 (d, 1H); 7.65 (d, 1H)

Example 47

[0799](5Z,7E)-(1S,3R)-1,3-Dihydroxy-24-(thiazol-2-yl)-9,10-secochola-5,7,10(19)-trien-24-one219

[0800] 210. 40 mg of alcohol 216 is treated analogously to 25., whereby24 mg of(5Z,7E)-(1S,3R)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24-(thiazol-2-yl)-9,10-secochola-5,7,10(19)-trien-24-one218 accumulates as a colorless foam. 0.146

[0801]¹H-NMR (CD₂Cl₂): δ=0.04 ppm (s, 12H); 0.52 (s, 3H); 0.84 (s, 18H);0.97 (d, 3H); 4.17 (m, 1H); 4.36 (m, 1H); 4.84 (s, 1H); 5.16 (s, 1H);6.01 (d, 1H); 6.23 (d, 1H); 7.65 (d, 1H); 7.97 (d, 1H)

[0802] 211. 24 mg of ketone 218 is treated analogously to 26., whereby14 mg of title compound 219 accumulates as a colorless foam.

[0803]¹H-NMR (CD₂Cl₂): δ=0.55 ppm (s, 3H); 0.99 (d, 3H); 4.15 (m, 1H);4.36 (m, 1H); 4.93 (s, 1H); 5.28 (s, 1H); 6.00 (d, 1H); 6.33 (d, 1H);7.65 (d, 1H); 7.98 (d, 1H)

Example 48

[0804](5Z,7E)-(1S,3R,24S)-24-(4-Methylthiazol-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol221a and(5Z,7E)-(1S,3R,24R)-24-(4-methylthiazol-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol221b

[0805] 212. 991 mg of 4-methylthiazole is introduced into 15 ml oftetrahydrofuran, and 4 ml of n-butyllithium solution (2.5 M in hexane)is added at −78° C. After 30 minutes at this temperature, 1.2 g ofaldehyde 215 in 8 ml of tetrahydrofuran is added in drops, and it isstirred for 1 more hour. Then, it is quenched with sodium chloridesolution, extracted with ethyl acetate, the organic phase is washed withsodium chloride solution and dried on sodium sulfate. The solvent isremoved, and the residue is chromatographed on silica gel with ethylacetate/hexane, whereby 1.03 g of(5Z,7E)-(1S,3R)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24-(4-methylthiazol-2-yl)-9,10-secochola-5,7,10(19)-trien-24-ol220 is obtained as a colorless oil.

[0806]¹H-NMR (CD₂Cl₂): δ=0.06 ppm (s, 12H); 0.53 (s, 3H); 0.87 (s, 18H);0.94 (d, 3H); 2.35 (s, 3H); 4.17 (m, 1H); 4.36 (m, 1H); 4.85 (s, 1H);4.86 (m, 1H); 5.17 (s, 1H); 6.01 (d, 1H); 6.23 (d, 1H); 6.83 (s, 1H).

[0807] 213. 250 mg of alcohol 220 is treated analogously to 14., andafter the diastereomers (in terms of C-24a) are separated by HPLC, 57 mgof title compound 221a and 63 mg of title compound 221b are obtained ascolorless foams.

[0808]¹H-NMR (CD₂Cl₂): 221a: δ=0.51 ppm (s, 3H); 0.93 (d, 3H); 2.36 (s,3H); 4.16 (m, 1H); 4.36 (m, 1H); 4.85 (m, 1H); 4.93 (s, 1H); 5.28 (s,1H); 6.00 (d, 1H); 6.33 (d, 1H); 6.81 (s, 1H)

[0809] 221b: δ=0.51 ppm (s, 3H); 0.93 (d, 3H); 2.36 (s, 3H); 4.16 (m,1H); 4.35 (m, 1H); 4.85 (m, 1H); 4.92 (s, 1H); 5.27 (s, 1H); 6.00 (d,1H); 6.33 (d, 1H); 6.82 (s, 1H)

Example 49

[0810](5Z,7E)-(1S,3R)-1,3-Dihydroxy-24-(4-methylthiazol-2-yl)-9,10-secochola-5,7,10(19)-trien-24-one223

[0811] 214. 70 mg of alcohol 220 is treated analogously to 25., whereby56 mg of(5Z,7E)-(1S,3R)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24-(4-methylthiazol-2-yl)-9,10-secochola-5,7,10(19)-trien-24-one222 accumulates as a colorless foam.

[0812]¹H-NMR (CD₂Cl₂) δ=0.04 ppm (s, 12H); 0.51 (s, 3H); 0.82 (s, 18H);0.95 (d, 3H); 2.44 (s, 3H); 4.16 (m, 1H); 4.35 (m, 1H); 4.82 (s, 1H);5.15 (s, 1H); 5.99 (d, 1H); 6.22 (d, 1H); 7.18 (s, 1H)

[0813] 215. 56 mg of ketone 222 is treated analogously to 26., whereby25 mg of title compound 223 accumulates as a colorless foam.

[0814]¹H-NMR (CD₂Cl₂): δ=0.54 ppm (s, 3H); 0.99 (d, 3H); 2.49 (s, 3H);4.16 (m, 1H); 4.38 (m, 1H); 4.94 (s, 1H); 5.28 (s, 1H); 6.00 (d, 1H);6.34 (d, 1H); 7.24 (d, 1H)

Example 50

[0815](5Z,7E)-(1S,3R,24S)-24-(Thien-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol225a and(5Z,7E)-(1S,3R,24R)-24-(thien-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol225b

[0816] 216. 450 mg of thiophene is introduced into 10 ml oftetrahydrofuran, and 2 ml of n-butyllithium solution (2.5 M in hexane)is added at −78° C. After 30 minutes at this temperature, 600 mg ofaldehyde 215 in 4 ml of tetrahydrofuran is added in drops, and it isstirred for 1 more hour. Then, it is quenched with sodium chloridesolution, extracted with ethyl acetate, the organic phase is washed withsodium chloride solution and dried on sodium sulfate. The solvent isremoved, and the residue is chromatographed on silica gel with ethylacetate/hexane, whereby 398 mg of(5Z,7E)-(1S,3R)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24-(thien-2-yl)-9,10-secochola-5,7,10(19)-trien-24-ol224 is obtained as a colorless oil.

[0817]¹H-NMR (CDCl₃): δ=0.06 ppm (s, 12H); 0.53 (s, 3H); 0.89 (s, 18H);0.94 (d, 3H); 4.18 (m, 1H); 4.38 (m, 1H); 4.86 (s, 1H); 4.86 (m, 1H);5.17 (s, 1H); 6.01 (d, 1H); 6.23 (d, 1H); 6.98 (m, 2H); 7.24 (m, 1H)

[0818] 217. 92 mg of alcohol 224 is treated analogously to 14., andafter the diastereomers (in terms of C-24a) are separated by HPLC, 21 mgof title compound 225a and 19 mg of title compound 225b are obtained ascolorless foams.

[0819]¹H-NMR (CD₂Cl₂) 225a: δ=0.51 ppm (s, 3H); 0.92 (d, 3H); 4.14 (m,1H); 4.34 (m, 1H); 4.83 (dd, 1H); 4.93 (s, 1H); 5.28 (s, 1H); 6.00 (d,1H); 6.33 (d, 1H); 6.92 (m, 2H); 7.22 (dd, 1H)

[0820] 225b: δ=0.51 ppm (s, 3H); 0.92 (d, 3H); 4.15 (m, 1H); 4.35 (m,1H); 4.84 (t, 1H); 4.92 (s, 1H); 5.27 (s, 1H); 6.00 (d, 1H); 6.33 (d,1H); 6.92 (m, 1H); 7.21 (dd, 1H)

Example 51

[0821](5Z,7E)-(1S,3R)-1,3-Dihydroxy-24-(thien-2-yl)-9,10-secochola-5,7,10(19)-trien-24-one227

[0822] 218. 70 mg of alcohol 224 is treated analogously to 25., whereby28 mg of(5Z,7E)-(1S,3R)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24-(thien-2-yl)-9,10-secochola-5,7,10(19)-trien-24-one226 accumulates as a colorless foam.

[0823]¹H-NMR (CD₂Cl₂): δ=0.05 ppm (s, 12H); 0.52 (s, 3H); 0.84 (s, 18H);0.95 (d, 3H); 4.16 (m, 1H); 4.35 (m, 1H); 4.83 (s, 1H); 5.15 (s, 1H);6.00 (d, 1H); 6.23 (d, 1H); 7.13 (t, 1H); 7.63 (d, 1H); 7.70 (d, 1H)

[0824] 219. 28 mg of ketone 226 is treated analogously to 26., whereby11 mg of title compound 227 accumulates as a colorless foam.

[0825]¹H-NMR (CD₂Cl₂): δ=0.54 ppm (s, 3H); 0.99 (d, 3H); 4.16 (m, 1H);4.38 (m, 1H); 4.95 (s, 1H); 5.28 (s, 1H); 6.00 (d, 1H); 6.35 (d, 1H);7.12 (dd, 1H); 7.62 (d, 1H); 7.71 (d, 1H)

Example 52

[0826](5Z,7E)-(1S,3R,24S)-24-(4-Methylthien-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol229a and(5Z,7E)-(1S,3R,24R)-24-(4-methylthien-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol229b

[0827] 220. 500 mg of 4-methylthiophene is introduced into 10 ml oftetrahydrofuran, and 2 ml of n-butyllithium solution (2.5 M in hexane)is added at −78° C. After 30 minutes at this temperature, 600 mg ofaldehyde 215 in 4 ml of tetrahydrofuran is added in drops, and it isstirred for 1 more hour. Then, it is quenched with sodium chloridesolution, extracted with ethyl acetate, the organic phase is washed withsodium chloride solution and dried on sodium sulfate. The solvent isremoved, and the residue is chromatographed on silica gel with ethylacetate/hexane, whereby 402 mg of(5Z,7E)-(1S,3R)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24-(4-methylthien-2-yl)-9,10-secochola-5,7,10(19)-trien-24-ol228 is obtained as a colorless oil.

[0828]¹H-NMR (CD₂Cl₂): δ=0.06 ppm (s, 12H); 0.55 (s, 3H); 0.86 (s, 18H);0.94 (d, 3H); 2.21 (s, 3H); 4.16 (m, 1H); 4.36 (m, 1H); 4.84 (s, 1H);4.86 (m, 1H); 5.16 (s, 1H); 6.01 (d, 1H); 6.23 (d, 1H); 6.74 (m, 1H);7.78 (m, 1H)

[0829] 221. 98 mg of alcohol 228 is treated analogously to 14., andafter the diastereomers (in terms of C-24a) are separated by HPLC, 22 mgof title compound 229a and 17 mg of title compound 229b are obtained ascolorless foams.

[0830]¹H-NMR (CD₂Cl₂): 229a: δ=0.52 ppm (s, 3H); 0.92 (d, 3H); 2.21 (s,3H); 4.15 (m, 1H); 4.35 (m, 1H); 4.86 (dd, 1H); 4.93 (s, 1H); 5.28 (s,1H); 5.99 (d, 1H); 6.33 (d, 1H); 6.84 (m, 1H); 6.89 (m, 1H)

[0831] 229b: δ=0.52 ppm (s, 3H); 0.92 (d, 3H); 2.22 (s, 3H); 4.15 (m,1H); 4.35 (m, 1H); 4.85 (t, 1H); 4.92 (s, 1H); 5.27 (s, 1H); 6.00 (d,1H); 6.33 (d, 1H); 6.84 (m, 1H); 6.88 (m, 1H)

Example 53

[0832](5Z,7E)-(1S,3R)-1,3-Dihydroxy-24-(4-methylthien-2-yl)-9,10-secochola-5,7,10(19)-trien-24-one231

[0833] 222. 65 mg of alcohol 228 is treated analogously to 25., whereby34 mg of(5Z,7E)-(1S,3R)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24-(4-methylthien-2-yl)-9,10-secochola-5,7,10(19)-trien-24-one230 accumulates as a colorless foam.

[0834]¹H-NMR (CD₂Cl₂): δ=0.05 ppm (s, 12H); 0.53 (s, 3H); 0.84 (s, 18H);0.94 (d, 3H); 2.33 (s, 3H); 4.16 (m, 1H); 4.35 (m, 1H); 4.83 (s, 1H);5.15 (s, 1H); 6.01 (d, 1H); 6.23 (d, 1H); 7.65 (s, 1H); 7.70 (s, 1H)

[0835] 223. 34 mg of ketone 230 is treated analogously to 26., whereby13 mg of title compound 231 accumulates as a colorless foam.

[0836]¹H-NMR (CD₂Cl₂): δ=0.54 ppm (s, 3H); 0.98 (d, 3H); 2.32 (s, 3H);4.16 (m, 1H); 4.37 (m, 1H); 4.95 (s, 1H); 5.28 (s, 1H); 6.00 (d, 1H);6.34 (d, 1H); 7.63 (s, 1H); 7.71 (s, 1H)

Example 54

[0837](7E)-(1R,3R,24aR)-24a-Fluoro-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3-diol236a and(7E)-(1R,3R,24aS)-24a-fluoro-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3-diol236b

[0838] 224. 1.0 g of alcohol 21 is introduced into 80 ml ofdichloromethane at −78° C., 0.044 ml of diethylaminosulfur trifluoride(DAST) is added, and it is stirred for 15 more minutes. It is quenchedwith sodium bicarbonate, extracted with dichloromethane and dried onsodium sulfate. After the concentration by evaporation and thechromatography on silica gel with ethyl acetate/hexane, 765 mg of[1R-[1α(1R*),3aβ,4α,7aα]]-1-[5-fluoro-1-methyl-5-(thiazol-2-yl)pentyl]octahydro-7a-methyl-4-[(triethylsilyl)oxy]-1H-indene232 is obtained as a colorless oil.

[0839]¹H-NMR (CDCl₃): δ=0.55 ppm (q, 6H); 0.90 (d, 3H); 0.91 (s, 3H);0.96 (t, 9H); 4.02 (m, 1H); 5.24 (dbr, 1H); 7.35 (d, 1H); 7.80 (t, 1H)

[0840] 225. 765 mg of compound 232 is treated analogously to 10., and505 mg of[1R-[1α(1R*),3aβ,4α,7aα]]-1-[5-fluoro-1-methyl-5-(thiazol-2-yl)pentyl]octahydro-7a-methyl-1H-inden-4-ol233 is obtained as a colorless oil.

[0841]¹H-NMR (CDCl₃): δ=0.90 ppm (d, 3H); 0.92 (s, 3H); 4.08 (m, 1H);5.75 (dbr, 1H); 7.38 (d, 1H); 7.80 (t, 1H)

[0842] 226. 505 mg of alcohol 233 is treated analogously to 11., and 468mg of[1R-[1α(1R*),3aβ,7aα]]-1-[5-fluoro-1-methyl-5-(thiazol-2-yl)pentyl]octahydro-7a-methyl-4H-inden-4-one234 is obtained as a colorless oil.

[0843]¹H-NMR (CDCl₃): δ=0.62 ppm (s, 3H); 0.98 (d, 3H); 2.45 (dd, 1H);5.75 (dbr, 1H); 7.38 (d, 1H); 7.80 (t, 1H)

[0844] 227. 676 mg of phosphine oxide 13, which was deprotonated with0.57 ml of n-butyllithium solution (2.5 M in hexane), is reacted with200 mg of ketone 234 analogously to 12., and 341 mg of(7E)-(1R,3R)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-fluoro-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene235 is obtained as a colorless foam.

[0845]¹H-NMR (CDCl₃): δ=0.06 ppm (s, 12H); 0.53 (s, 3H); 0.89 (s, 18H);0.93 (d, 3H); 4.09 (m, 2H); 5.75 (dbr, 1H); 5.82 (d, 1H); 6.18 (d, 1H);7.39 (d, 1H); 7.80 (t, 1H)

[0846] 228. 331 mg of fluoride 235 is treated analogously to 14., andafter the diastereomers (in terms of C-24a) are separated by HPLC, 67 mgof title compound 236a and 69 mg of title compound 236b are obtained ascolorless foams.

[0847]¹H-NMR (CD₂Cl₂): 236a: δ=0.52 ppm (s, 3H); 0.91 (d, 3H); 3.98 (m,1H); 4.05 (m, 1H); 5.73 (dbr, 1H); 5.85 (d, 1H); 6.27 (d, 1H); 7.40 (d,1H); 7.78 (t, 1H)

[0848] 236b: δ=0.52 ppm (s, 3H); 0.91 (d, 3H); 3.97 (m, 1H); 4.04 (m,1H); 5.74 (dbr, 1H); 5.85 (d, 1H); 6.27 (d, 1H); 7.40 (d, 1H); 7.78 (t,1H)

Example 55

[0849](5Z,7E)-(1S,3R,24aR)-24a-Fluoro-24a-(thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3-diol238a and(5Z,7E)-(1S,3R,24aS)-24a-fluoro-24a-(thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3-diol238b

[0850] 229. 517 mg of phosphine oxide 17, which was deprotonated with0.42 ml of n-butyllithium solution (2.5 M in hexane), is reacted with150 mg of ketone 234 analogously to 15., and 293 mg of(5Z,7E)-(1S,3R)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-fluoro-24a-(thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene237 is obtained as a colorless foam.

[0851]¹H-NMR (CDCl₃): δ=0.07 ppm (s, 12H); 0.54 (s, 3H); 0.92 (s, 18H);0.96 (d, 3H); 4.20 (m, 1H); 4.39 (m, 1H); 4.89 (s, 1H); 5.20 (s, 1H);5.77 (dbr, 1H); 6.05 (d, 1H); 6.25 (d, 1H); 7.40 (d, 1H); 7.80 (t, 1H)

[0852] 230. 283 mg of fluoride 237 is treated analogously to 14., andafter the diastereomers (in terms of C-24a) are separated by HPLC, 67 mgof title compound 238a and 59 mg of title compound 238b are obtained ascolorless foams.

[0853]¹H-NMR (CD₂Cl₂): 238a: δ=0.52 ppm (s, 3H); 0.92 (d, 3H); 4.18 (m,1H); 4.38 (m, 1H); 4.95 (s, 1H); 5.28 (s, 1H); 5.72 (dbr, 1H); 6.00 (d,1H); 6.36 (d, 1H); 7.40 (d, 1H); 7.80 (t, 1H)

[0854] 238b: δ=0.51 ppm (s, 3H); 0.89 (d, 3H); 4.11 (m, 1H); 4.33 (m,1H); 4.90 (t, 1H); 4.92 (s, 1H); 5.27 (s, 1H); 6.00 (d, 1H); 6.32 (d,1H); 7.29 (d, 1H); 7.68 (d, 1H)

Example 56

[0855](7E)-(1R,3R,24aR)-24a-(Acetyloxy)-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol239a and(7E)-(1R,3R,24aS)-24a-(acetyloxy)-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol239b

[0856] 231. 117 mg of acetate 25 is introduced into 6 ml oftetrahydrofuran, 0.9 ml of hydrogen fluoride-pyridine complex is added,and it is stirred for 4 hours at 25° C. The mixture is mixed with sodiumbicarbonate solution, extracted with ethyl acetate, and the organicphase is washed with sodium chloride solution. After drying on sodiumsulfate, the solvent is removed, and the residue is chromatographed onsilica gel with ethyl acetate/hexane, whereby 72 mg of title compounds239a and 239b are obtained as colorless oils. The separation ofdiastereomers is carried out on HPLC and yields 31 mg of title compound239a and 26 mg of title compound 239b as colorless foams.

[0857]¹H-NMR (CD₂Cl₂): 239a: δ=0.51 ppm (s, 3H); 0.88 (d, 3H); 2.11 (s,3H); 3.98 (m, 1H); 4.05 (m, 1H); 5.84 (d, 1H); 6.04 (dd, 1H); 6.37 (d,1H); 7.31 (d, 1H); 7.71 (d, 1H)

[0858] 239b: δ=0.51 ppm (s, 3H); 0.89 (d, 3H); 2.12 (s, 3H); 3.98 (m,1H); 4.06 (m, 1H); 5.84 (d, 1H); 6.05 (dd, 1H); 6.37 (d, 1H); 7.31 (d,1H); 7.71 (d, 1H)

Example 57

[0859](7E)-(1R,3R,24aR)-24a-(2,2-Dimethyl-1-oxopropyl)oxy-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol241a and(7E)-(1R,3R,24aS)-24a-(2,2-dimethyl-1-oxopropyl)oxy-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol241b

[0860] 232. 200 mg of alcohol 26 is introduced into 6 ml of pyridine,and it is stirred for 5 hours at 25° C. Then, it is quenched with sodiumbicarbonate solution, extracted with ethyl acetate, and the organicphase is washed with sodium chloride solution. After drying on sodiumsulfate, the solvent is removed, and the residue is chromatographed onsilica gel with ethyl acetate/hexane, whereby 1120 mg of(7E)-(1R,3R)-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-24a-(2,2-dimethyl-1-oxopropyl)oxy-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene240 is obtained as a colorless foam.

[0861]¹H-NMR (CD₂Cl₂): δ=0.07 ppm (s, 3H); 0.53 (s, 3H); 0.89 (s, 18H);0.92 (d, 3H); 1.23 (s, 9H); 3.98 (m, 1H); 4.05 (m, 1H); 5.84 (d, 1H);6.03 (dd, 1H); 6.37-(d, 1H); 7.31 (d, 1H); 7.71 (d, 1H)

[0862] 233. 120 mg of pivalate 240 is introduced into 7 ml oftetrahydrofuran, 0.4 ml of hydrogen fluoride-pyridine complex is added,and it is stirred for 4 hours at 25° C. The mixture is mixed with sodiumbicarbonate solution, extracted with ethyl acetate, and the organicphase is washed with sodium chloride solution. After drying on sodiumsulfate, the solvent is removed, and the residue is chromatographed onsilica gel with ethyl acetate/hexane, whereby 74 mg of title compounds241a and 241b are obtained as colorless oils. The separation of thediastereomers is carried out on HPLC and yields 28 mg of title compound241a and 27 mg of title compound 241b as colorless foams.

[0863]¹H-NMR (CD₂Cl₂): 241a: δ=0.51 ppm (s, 3H); 0.88 (d, 3H); 1.24 (s,9H); 3.98 (m, 1H); 4.05 (m, 1H); 5.84 (d, 1H); 6.05 (dd, 1H); 6.37 (d,1H); 7.30 (d, 1H); 7.72 (d, 1H)

[0864] 241b: δ=0.51 ppm (s, 3H); 0.88 (d, 3H); 1.23 (s, 9H); 3.98 (m,1H); 4.06 (m, 1H); 5.84 (d, 1H); 6.05 (dd, 1H); 6.37 (d, 1H); 7.31 (d,1H); 7.72 (d, 1H)

Example 58

[0865] (3R,5R)-3,5-Bis(benzoyloxy)-4-bromo-cyclohexan-1-one 234.

[0866] 17.9 g of starting compound XXIX (synthesized according to J. -L.Montchamp, J. W. Frost J. Am. Chem. Soc. 113, 6296 (1991)) is dissolvedin 500 ml of benzene. Then, 11.26 g of N-bromosuccinimide and a spatulatip full of AIBN are added and stirred for 1.5 hours. The almostbleached solution is extracted with ethyl acetate, washed with Na₂S₂O₃solution and then washed with sodium chloride solution, dried andconcentrated by evaporation. Column chromatography with hexane/ethylacetate (1:1) yields 14.7 g of bromated product XXXb.

[0867] 235.

[0868] 14.7 g of alcohol XXXb is introduced into 350 ml of pyridine andmixed with 12.8 ml of benzoyl chloride and a spatula tip full of DMAP(4-dimethylaminopyridine) and stirred for 12 hours at room temperature.Sodium bicarbonate is carefully added to the reaction mixture, stirredfor 30 minutes, extracted with methylene chloride, dried on sodiumsulfate and concentrated by evaporation. Column chromatography withethyl acetate/hexane (1:9) yields 15.4 g of diester XXXIb. 236.

[0869] 15.4 g of diester, XXXIb from 235. is dissolved in 300 ml ofmethanol and mixed with 5.9 g of p-toluenesulfonic acid. The batch isstirred for 12 hours at room temperature. After 1 l of ethyl acetate isadded, it is washed four times with sodium chloride solution, dried onsodium sulfate and concentrated by evaporation. Column chromatographywith hexane/ethyl acetate yields 9.2 g of diol XXXIIb.

[0870] 237.

[0871] 5 g of diol XXXIIb that is obtained from 236. is introduced into200 ml of methanol. 8.31 g of sodium periodate in 60 ml of water isadded in drops, and then it is stirred for one hour at 0° C. It isquenched with sodium chloride solution, extracted with ethyl acetate,dried and concentrated by evaporation. 4.68 g of crude product XXXIIIbis obtained, which is used without further purification in the Wittigreaction (Example 59, instructions 243, and 60, instructions 249).

Example 59

[0872](7E)-(1R,3R)-2-Bromo-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0873] 238.[1R-[1α(1R*),3aβ,7aα]]-1-[5-(Hydroxy)-1-methyl-5-(thiazol-2-yl)pentyl]octahydro-7a-methyl-4H-inden-4-one

[0874] 500 mg of[1R-[1α(1R*),3aβ,7aα]]-1-[5-(acetyloxy)-1-methyl-5-(thiazol-2-yl)pentyl]octahydro-7a-methyl-4H-inden-4-one12 that can be obtained according to Example 1 is introduced into 30 mlof methanol and mixed with 800 mg of potassium carbonate. After 24 hoursof stirring at room temperature, it is mixed with methylene chloride andwashed with sodium chloride solution. After chromatography on silica gelwith ethyl acetate/hexane, 440 mg of[1R-[1α(1R*),3aβ,7aα]]-1-[5-(hydroxy)-1-methyl-5-(oxazol-4-yl)pentyl]octahydro-7a-methyl-4H-inden-4-oneis obtained.

[0875] 239.[1R-[1α(1R*),3aβ,7aα]]-Octahydro-7a-methyl-1-[1-methyl-5-(thiazol-2-yl)-5-[(triethylsilyl)oxy]pentyl]-4H-inden-4-one

[0876] 435 mg of[1R-[1α(1R*),3aβ,7aα]]-1-[5-(hydroxy)-1-methyl-5-(thiazol-2-yl)pentyl]octahydro-7a-methyl-4H-inden-4-oneis mixed in 7 ml of DMF with 0.31 ml of chlorotriethylsilane and 151 mgof imidazole, and it is stirred for three days at room temperature.After extraction with ethyl acetate, washing with sodium chloridesolution and drying, it is chromatographed with ethyl acetate/hexane.584 mg of[1R-[1α(1R*),3aβ,7aα]]-octahydro-7a-methyl-1-[1-methyl-5-(thiazol-2-yl)-5-[(triethylsilyl)oxy]-pentyl]-4H-inden-4-oneis obtained.

[0877] 240.[[1R-[1α(1R*),3aβ,7aα]]-[5-[(Triethylsilyl)oxy]-1-methyl-5-(thiazol-2-yl)pentyl]octahydro-7a-methyl-1H-inden-4-ylidine]aceticAcid Ethyl Ester

[0878] Lithium diisopropyl amide is produced from 0.7 ml ofdiisopropylamine and 2 ml of n-butyllithium (2.5 M in hexane) in 14 mlof tetrahydrofuran, cooled to −78° C., and 0.95 ml of trimethylaceticacid ethyl ester in 1 ml of tetrahydrofuran is added in drops. After 20minutes of stirring at −78° C., 584 mg of[1R-[1α(1R*),3aβ,7aα]]-octahydro-7a-methyl-1-[1-methyl-5-(thiazol-2-yl)-5-[(triethylsilyl)oxy]pentyl]-4H-inden-4-onein 2 ml of tetrahydrofuran is added. The reaction mixture is stirred at−78° C. until the reaction is completed according to TLC monitoring(ethyl acetate/hexane 2:8). After heating to room temperature, it isquenched with sodium chloride solution and extracted with ethyl acetate,the organic phase is washed with sodium chloride solution, dried onsodium sulfate and concentrated by evaporation. The residue ischromatographed with ethyl acetate/hexane on silica gel, whereby 700 mgof[[1R[1α(1R*),3aβ,7aα]]-1-[5-[(triethylsilyl)oxy]-1-methyl-5-(thiazol-2-yl)pentyl]octahydro-7a-methyl-1H-inden-4-ylidene]aceticacid ethyl ester is obtained.

[0879] 241.2-[[1R-[1α(1R*),3aβ,7aα]]-1-[5-[(Triethylsilyl)oxy]-1-methyl-5-(thiazol-2-yl)pentyl]octahydro-7a-methyl-1H-inden-4-ylidene]ethanol

[0880] 700 mg of[[1R-[1α(1R*),3aβ,7aα]]-1-[5-[(triethylsilyl)oxy]-1-methyl-5-(thiazol-2-yl)pentyl]octahydro-7a-methyl-1H-inden-4-ylidene]aceticacid ethyl ester is introduced into 30 ml of tetrahydrofuran at −20° C.,and 4.3 ml of diisobutyl aluminum hydride solution is added in drops. Itis stirred for 3 hours at −20° C. and then slowly heated to 0° C., and0.6 ml of diisobutyl aluminum hydride solution is added once more. After1 hour of stirring at 0° C., toluene is added, quenched with 1.5 ml ofisopropanol/water (1:9) and suctioned off on Celite. The residue isconcentrated by evaporation and chromatographed on silica gel (ethylacetate/hexane). 385 mg of2-[[1R-[1α(1R*),3aβ,7aα]]-1-[5-[(triethylsilyl)oxy]-1-methyl-5-(thiazol-2-yl)pentyl]octahydro-7a-methyl-1H-inden-4-ylidene]ethanolis obtained.

[0881] 242.[2-[1R-[1α(1R*),3aβ,7aα]]-1-[1-Methyl-5-(thiazol-2-yl)-5-[(triethylsilyl)oxy]pentyl]octahydro-7a-methyl-1H-indenylidene]ethyl]diphenylphosphineOxide

[0882] a) 385 mg of the alcohol2-[[1R-[1α(1R*),3aβ,7aα]]-1-[5-[(triethylsilyl)oxy]-1-methyl-5-(thiazol-2-yl)pentyl]octahydro-7a-methyl-1H-inden-4-ylidene]-ethanolthat is obtained from D is introduced into 2.5 ml of tetrahydrofuran at0° C. and mixed drop by drop with 0.35 ml of n-butyllithium at 0° C.Then, 166 mg of tosyl chloride in 0.5 ml of tetrahydrofuran is added indrops and stirred for at least 5 more minutes at 0° C.

[0883] b) In a second flask, 0.3 ml of diphenylphosphine is introducedinto 2 ml of tetrahydrofuran at 0° C. With dropwise addition of 0.7 mlof n-butyllithium, the solution is colored orange.

[0884] c) At 0° C., solution b) is now slowly added in drops to solutiona) and stirred for 30 more minutes at 0° C. Then, it is quenched withwater, the solution is concentrated by evaporation and taken up with alittle methylene chloride. After cooling to 0° C., 0.3 ml of 10%hydrogen peroxide solution is added and stirred for one more hour at 0°C. Then, it is quenched with sodium thiosulfate solution, washed withsodium chloride solution and dried. After column chromatography, 471 mgof[2-[1R[1α(1R*),3aβ,7aα]]-1-[1-methyl-5-(thiazol-2-yl)-5-[(triethylsilyl)oxy]pentyl]octahydro-7a-methyl-1H-indenylidene]ethyl]diphenylphosphineoxide is obtained.

[0885] 243.(7E)-(1R,3R)-1,3-Bis-(benzoyloxy)-2-bromo-24a-(thiazol-2-yl)-24a-[(triethylsilyl)oxy]-24a-homo-19-nor-9,10-secochola-5,7-diene

[0886] 471 mg of[2-[1R-[1α(1R*),3aβ,7aα]]-1-[1-methyl-5-(thiazol-2-yl)-5-[(triethylsilyl)oxy]-pentyl]octahydro-7a-methyl-1H-indenylidene]ethyl]diphenylphosphineoxide is introduced into 7 ml of tetrahydrofuran and cooled to −78° C.At this temperature, 0.26 ml of n-butyllithium solution is added andstirred for 10 more minutes at −30° C. Then, 446 mg of the ketone thatis obtained from Example 57, instructions 235, is added into 3 ml oftetrahydrofuran as a crude product and stirred for 5 more hours at −30°C. (TLC monitoring of hexane/ethyl acetate 6:4). It is quenched withsodium chloride solution, extracted with ethyl acetate, washed withsodium chloride solution, dried on sodium sulfate and concentrated byevaporation. 913 mg of crude product(7E)-(1R,3R)-1,3-bis(benzoyloxy)-2-bromo-24a-(thiazol-2-yl)-24a-[(triethylsilyl)oxy]-24a-homo-19-nor-9,10-secochola-5,7-dieneis obtained, which is further reacted without purification.

[0887] 244.(7E)-(1R,3R)-1,3-Bis-(benzoyloxy)-2-bromo-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-ol

[0888] 913 mg of crude product from Example 58F is introduced into 20 mlof tetrahydrofuran and mixed with 878 mg of tetrabutylammoniumfluoride-hydrate. After 2 hours of stirring at room temperature, sodiumbicarbonate solution is added, extracted with ethyl acetate, the organicphase is washed with sodium chloride solution and dried on sodiumsulfate. After concentration by evaporation, the residue is furtherreacted as a crude product. 134 mg of(7E)-(1R,3R)-1,3-bis-(benzoyloxy)-2-bromo-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-olis obtained as a crude product.

[0889] 245.(7E)-(1R,3R)-2-Bromo-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol

[0890] 134 mg of(7E)-(1R,3R)-1,3-bis-(benzoyloxy)-2-bromo-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-olis introduced into 5 ml of tetrahydrofuran at 78° C., mixed with 0.44 mlof DIBAH/tetrahydrofuran, allowed to heat to 0° C., and stirring iscontinued after repeated addition of 3 ml of DIBAH. It is quenched withsodium chloride, extracted with ethyl acetate, dried on sodium sulfateand concentrated by evaporation. The crude product is chromatographed onsilica gel. 24 mg of(7E)-(1R,3R)-2-bromo-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triolis obtained.

Example 60

[0891](7E)-(1R,3R)-2-Bromo-19-nor-9,10-secocholesta-5,7-diene-1,3,25-triol

[0892] 246.[[1R-[1α(1R*),3aβ,7aα]]-1-[1,5,5-Trimethyl-5-[(trimethylsilyl)oxy]pentyl]octahydro-7a-methyl-1H-inden-4-ylidene]aceticAcid Ethyl Ester

[0893] 1.0 g of the compound[[1R-[1α(1R*),3aβ,7aα]]-1-[1,5,5-trimethyl-5-[(trimethylsilyl]oxy]pentyl]octahydro-7a-methyl-4H-inden-4-onethat is known in the literature is reacted analogously to Example 59,instructions 240, and 1.03 g of[[1R[1α(1R*),3aβ,7aα]]-1-[1,5,5-trimethyl-5-[(trimethylsilyl)oxy]pentyl]octahydro-7a-methyl-1H-inden-4-ylidene]aceticacid ethyl ester is obtained.

[0894]¹H-NMR (CDCl₃): δ=0.1 ppm (s, 9H); 0.59 ppm (s, 3H); 0.95 (d, 3H);1.19 (s, 6H); 1.29 (t, 3H); 4.1 (q, 2H); 5.45 (s, 1H)

[0895] 247.2-[[1R-[1α(1R*),3aβ,7aα]]-1-[1,5,5-Trimethyl-5-[(trimethylsilyl)oxy]pentyl]-octahydro-7a-methyl-1H-inden-4-ylidene]ethanol

[0896] 1.03 g of the compound that is obtained from Example 60,instructions 246, is reacted analogously to Example 59, instructions241, and 535 mg of2-[[1R-[1α(1R*),3aβ,7aα]]-1-[1,5,5-trimethyl-5-[(trimethylsilyl)oxy]pentyl]octahydro-7a-methyl-1H-inden-4-ylidene]ethanolis obtained.

[0897]¹H-NMR (CDCl₃): δ=0.1 ppm (s, 9H); 0.57 (s, 3H); 0.91 (d, 3H); 1.2(s, 6H); 4.21 (d, 2H); 5.23 (t, 1H)

[0898] 248.[1R-1α(1R*),3aβ,7aα]]-1-[5-[(Triethylsilyl)oxy]-1,5,5-trimethyl-5-(trimethyl-silyloxy)pentyl]octahydro-7a-methyl-1H-indenylidene]ethyl]diphenylphosphineOxide

[0899] 535 mg of2-[[1R-[1α(1R*),3aβ,7aα]]-1-[1,5,5-trimethyl-5-[(trimethylsilyl)oxy]pentyl]-octahydro-7a-methyl-1H-inden-4-ylidene]ethanolis reacted analogously to Example 59, instructions 242, and 318 mg of[1R-[1α(1R*),3aβ,7aα]]-1-[5-[(triethylsilyl)oxy]-1,5,5-trimethyl-5-(trimethylsilyloxy)pentyl]octahydro-7a-methyl-1H-indenylidene]ethyl]-diphenylphosphineoxide is obtained.

[0900]¹H-NMR (CDCl₃): δ=0.1 ppm (s, 9H); 0.3 (s, 3H); 0.88 (d, 3H); 1.2(s, 6H); 3.05-3.34 (m, 2H); 5.0 (m, 1H); 7.45 (m, 6H); 7.73 (m, 4H)

[0901] 249.(7E)-(1R,3R)-1,3-Bis(benzoyloxy)-2-bromo-25-[(trimethylsilyl)oxy]-19-nor-9,10-secocholesta-5,7-diene

[0902] 445 mg of(7E)-(1R,3R)-1,3-bis(benzoyloxy)-2-bromo-25-[(trimethylsilyl)oxy]-19-nor-9,10-seococholesta-5,7-dieneis obtained from 210 mg of[1R-[1α(1R*),3aβ,7aα]]-1-[5-[(triethylsilyl)oxy]-1,5,5-trimethyl-5-(trimethylsilyloxy)-pentyl]octahydro-7a-methyl-1H-indenylidene]ethyl]diphenyl-phosphineoxide analogously to Example 59, instructions 243.

[0903]¹H-NMR (CDCl₃): δ=0.1 ppm (s, 9H); 0.24 (s, 3H); 0.89 (d, 3H);1.18 (s, 6H)

[0904] 250.(7E)-(1R,3R)-1,3-Bis(benzoyloxy)-2-bromo-19-nor-9,10-secocholesta-5,7-dien-25-ol

[0905] 170 mg of(7E)-(1R,3R)-1,3-bis(benzoyloxy)-2-bromo-19-nor-9,10-secocholesta-5,7-dien-25-ol,which is further reacted without purification, is obtained from 445 mgof(7E)-(1R,3R)-1,3-bis(benzoyloxy)-2-bromo-25-[(trimethylsilyl)oxy]-19-nor-9,10-secocholesta-5,7-dieneanalogously to Example 59, instructions 244.

[0906] 251.(7E)-(1R,3R)-2-Bromo-19-nor-9,10-secocholesta-5,7-diene-1,3,25-triol

[0907] 35 mg of(7E)-(1R,3R)-2-bromo-19-nor-9,10-secocholesta-5,7-diene-1,3,25-triol isobtained from 151 mg of(7E)-(1R,3R)-1,3-bis(benzoyloxy)-2-bromo-25-[(trimethylsilyl)oxy]-19-nor-9,10-secocholesta-5,7-dieneanalogously to Example 59, instructions 245.

[0908]¹H-NMR (CDCl₃): δ=0.52 ppm (s, 3H); 0.92 (d, 3H); 1.14 (s, 6H);3.8 (d, 1H); 3.95-4.08 (2×m, 2H); 4.19 (dd, 1H); 6.27 (d, 1H)

1. Vitamin D derivatives of general formula I,

in which Y₁ and Y₂, independently of one another, each mean a hydrogenatom or a group —C(O)R₅, and Y₃ means a hydrogen atom or a hydroxygroup, a halogen atom, a group —OC(O)R₅ or an —OR₅ group, whereby R₅stands for an aromatic radical with 5 to 12 C atoms or for an aliphatic,straight-chain or branched, saturated or unsaturated C₁-C₁₂ alkylradical, which optionally is interrupted by 1-2 oxygen atoms, 1-2 sulfuratoms and/or 1-2 NH groups and/or optionally is substituted by 1-2hydroxy groups, 1-2 amino groups, 1-2 SH groups, 1-2 COOH groups and/or1-2 phenyl groups, and group Y₃ can be present both in the 2α-situationand the epimeric 2β-situation, R₁ and R₂ each mean a hydrogen atom ortogether an exocyclic methylene group, R₃ and R₄, independently of oneanother, each mean a hydrogen atom, a fluorine, chlorine or bromineatom, an alkyl group with 1 to 4 carbon atoms, together a methylenegroup or together with quaternary carbon atom 20 a 3- to 7-membered,saturated or unsaturated carbocyclic ring, Q means a straight-chainalkylene group with 1 to 5 carbon atoms, X₁ and X₂ together mean adouble-bound keto-oxygen atom or, independently of one another, ahydrogen atom, a hydroxy group, an —O(CO)R₅ group, a fluorine, chlorineor bromine atom, whereby X₁ and X₂, not at the same time, each should bea hydroxy group or each an —O(CO)R₅ group, Z means a carbocyclic orheterocyclic, optionally aromatic or heteroaromatic ring with 5 or 6ring members or a condensed ring system that consists of a 5- and a6-membered ring or two 6-membered rings, which can be substituted by oneor more fluorine, chlorine, bromine or iodine atoms, one or more hydroxygroups, one or more COOR₆ groups, one or more C₁-C₅ alkyl groups, whichin turn can be substituted by one or more fluorine, chlorine, bromine oriodine atoms, C₁-C₆ alkoxy groups and/or COOR₆ groups, whereby R₆ standsfor a C₁-C₆ alkyl group, a benzyl group or a phenyl group, and allpossible epimers or diastereomers and mixtures thereof.
 2. Compounds ofgeneral formula I according to claim 1, in which R₃ or R₄ meanshydrogen, X₁ and X₂ together mean a carbonyl group, or X₁ means ahydroxyl group or a fluorine atom and X₂ means a hydrogen atom or X₁means a hydrogen atom and X₂ means a hydroxyl group or a fluorine atomor X₁ means an —OC(O)R₅ group and X₂ means a hydrogen atom or X₁ means ahydrogen atom and X₂ means an —OC(O)R₅ group, and X represents anaromatic ring system.
 3. Compounds of general formula I according toclaim 1, in which R₃ or R₄ means hydrogen, X₁ and X₂ together mean acarbonyl group, or X₁ means a hydroxyl group or a fluorine atom and X₂means a hydrogen atom or X₁ means a hydrogen atom and X₂ means ahydroxyl group or a fluorine atom or X₁ means an —OC(O)R₅ group and X₂means a hydrogen atom or X₁ means a hydrogen atom and X₂ means an—OC(O)R₅ group, and Z represents a heteroaromatic ring system. 4.Compounds according to claim 1, in which the stereochemistry in20-position in the unnatural 20-epi-configuration is present.
 5. VitaminD derivatives of general formula I according to claim 1,(7E)-(1R,3R,24aR)-24a-(Oxazol-4-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R,24as)-24a-(oxazol-4-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(5Z,7E)-(1S,3R,24aR)-24a-(oxazol-4-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol(5Z,7E)-(1S,3R,24aS)-24a-(oxazol-4-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol(7E)-(1R,3R,24aR)-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R,24aS)-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R)-1,3-dihydroxy-24a-(thiazol-2-yl)-24-a-homo-19-nor-9,10-secochola-5,7-dien-24a-one(5Z,7E)-(1S,3R,24aR)-24a-(thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol(5Z,7E)-(1S,3R,24aS)-24a-(thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol(5Z,7E)-(1S,3R)-1,3-dihydroxy-24a-(thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one(7E)-(1R,3R,24aR)-24a-(4-methylthiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R,24aS)-24a-(4-methylthiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R)-1,3-dihydroxy-24a-(4-methylthiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one(5Z,7E)-(1S,3R,24aR)-24a-(4-methylthiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol(5Z,7E)-(1S,3R,24aS)-24a-(4-methylthiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol(5Z,7E)-(1S,3R)-1,3-dihydroxy-24a-(4-methylthiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one(7E)-(1R,3R,24aR)-24a-(thien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R,24aS)-24a-(thien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R)-1,3-dihydroxy-24a-(thien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one(5Z,7E)-(1S,3R,24aR)-24a-(thien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol(5Z,7E)-(1S,3R,24aS)-24a-(thien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol(7E)-(1R,2S,3R,24aR)-24a-thien-2-yl-24a-homo-19-nor-9,10-secochola-5,7-diene-1,2,3,24-tetrol(7E)-(1R,2S,3R,24aS)-24a-thien-2-yl-24a-homo-19-nor-9,10-secochola-5,7-diene-1,2,3,24-tetrol(7E)-(1R,2S,3R)-24a-thien-2-yl-1,2,3-trihydroxy-24a-homo-9,10-secochola-5,7-dien-24a-one(7E)-(1R,3R,24aR)-24a-(4-methylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R,24aS)-24a-(4-methylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R)-1,3-dihydroxy-24a-(4-methylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one(5Z,7E)-(1S,3R,24aR)-24a-(4-methylthien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol(5Z,7E)-(1S,3R,24aS)-24a-(4-methylthien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol(5Z,7E)-(1S,3R)-1,3-dihydroxy-24a-(4-methylthien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one(7E)-(1R,2S,3R,24aR)-24a-(4-methylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,2,3,24-tetrol(7E)-(1R,2S,3R,24aS)-24a-(4-methylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,2,3,24-tetrol(7E)-(1R,2S,3R)-24a-(4-methylthien-2-yl)-1,2,3-trihydroxy-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one(7E)-(1R,3R,24aR)-24a-(5-ethylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R,24aS)-24a-(5-ethylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R,24aR)-24a-[5-(2-hydroxyethyl)-4-methylthiazol-2-yl]-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R,24aS)-24a-[5-(2-hydroxyethyl)-4-methylthiazol-2-yl]-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R)-1,3-dihydroxy-24a-[5-(2-hydroxyethyl)-4-methylthiazol-2-yl]-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one(7E)-(1R,3R,24aR)-24a-(benzothiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R,24aS)-24a-(benzothiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R)-24a-(benzothiazol-2-yl)-1,3-dihydroxy-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one(7E)-(1R,3R,24aR)-24a-(benzofuran-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R,24aS)-24a-(benzofuran-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R)-24a-(benzofuran-2-yl)-1,3-dihydroxy-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one(7E)-(1R,3R,24aR)-24a-(benzothiophen-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R,24aS)-24a-(benzothiophen-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R)-24a-(benzothiophen-2-yl)-1,3-dihydroxy-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one(7E)-(1R,3R,24aR)-24a-(1-methylbenzimidazol-2-yl)-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R,24aS)-24a-(1-methylbenzimidazol-2-yl)-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R)-1,3-dihydroxy-24a-(1-methylbenzimidazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one(7E)-(1R,3R)-1-(1,3-dihydroxy-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-yl)-3-[(4-methoxyphenyl)-methoxy]-1H-pyrazole-4-carboxylicacid ethyl ester(7E)-(1R,3R)-1-(1,3-dihydroxy-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-yl)-3-hydroxy-1H-pyrazole-4-carboxylicacid ethyl ester(7E)-(1R,3R,24aR)-24a-(4-methylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R,24aS)-24a-(4-methylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R)-1,3-dihydroxy-24a-(4-methylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one(7E)-(1R,2R,3R,24aR)-24a-(4-methylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,2,3,24a-tetrol(7E)-(1R,RS,3R,24aS)-24a-(4-methylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,2,3,24a-tetrol(7E)-(1R,3R,24aR)-24a-(4-trifluoromethylphenyl)-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R,24aS)-24a-(4-trifluoromethylphenyl)-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R)-1,3-dihydroxy-24a-(4-trifluoromethylphenyl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one(7E)-(1R,3R,24aR)-24a-(4-methoxyphenyl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R,24aS)-24a-(4-methoxyphenyl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R)-1,3-dihydroxy-24a-(4-methoxyphenyl)-24a-homo-19-nor-9,10-secochola-5,7-dien-24a-one(7E)-(1R,3R,20S,24aR)-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R,20S,24aS)-24a-(thiazol-2-yl)-24-a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R,20S)-1,3-dihydroxy-24a-(thiazol-2-yl)-24-a-homo-19-nor-9,10-secochola-5,7-dien-24a-one(5Z,7E)-(1S,3R,20S,24aR)-24a-(thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol(5Z,7E)-(1S,3R,20S,24aS)-24a-(thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol(5Z,7E)-(1S,3R,20S)-1,3-dihydroxy-24a-(thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one(5Z,7E)-(1S,3R,24S)-24-(thiazol-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol(5Z,7E)-(1S,3R,24R)-24-(thiazol-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol(5Z,7E)-(1S,3R)-1,3-dihydroxy-24-(thiazol-2-yl)-9,10-secochola-5,7,10(19)-trien-24-one(7E)-(1R,3R,20S,24aR)-24a-(oxazol-4-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R,20S,24aS)-24a-(oxazol-4-yl)-24-a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R,20S)-1,3-dihydroxy-24a-(oxazol-4-yl)-24-a-homo-19-nor-9,10-secochola-5,7-dien-24a-one(5Z,7E)-(1S,3R,2,0S,24aR)-24a-(oxazol-4-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol(5Z,7E)-(1S,3R,20S,24aS)-24a-(oxazol-4-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol(5Z,7E)-(1S,3R,20S)-1,3-dihydroxy-24a-(oxazol-4-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one(5Z,7E)-(1S,3R,24R)-24-(oxazol-4-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol(5Z,7E)-(1S,3R,24S)-24-(oxazol-4-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol(5Z,7E)-(1S,3R)-1,3-dihydroxy-24-(oxazol-4-yl)-9,10-secochola-5,7,10(19)-trien-24-one(7E)-(1R,3R,20S,24aR)-24a-(4-methylthiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R,20S,24aS)-24a-(4-methylthiazol-2-yl)-24-a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R,20S)-1,3-dihydroxy-24a-(4-methylthiazol-2-yl)-24-a-homo-19-nor-9,10-secochola-5,7-dien-24a-one(5Z,7E)-(1S,3R,20S,24aR)-24a-(4-methylthiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol(5Z,7E)-(1S,3R,20S,24aS)-24a-(4-methylthiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol(5Z,7E)-(1S,3R,20S)-1,3-dihydroxy-24a-(4-methylthiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one(5Z,7E)-(1S,3R,24R)-24-(4-methylthiazol-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol(5Z,7E)-(1S,3R,24S)-24-(4-methylthiazol-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol(5Z,7E)-(1S,3R)-1,3-dihydroxy-24-(4-methylthiazol-2-yl)-9,10-secochola-5,7,10(19)-trien-24-one(7E)-(1R,3R,20S,24aR)-24a-(4-methylthien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R,20S,24aS)-24a-(4-methylthien-2-yl)-24-a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R,20S)-1,3-dihydroxy-24a-(4-methylthien-2-yl)-24-a-homo-19-nor-9,10-secochola-5,7-dien-24a-one(5Z,7E)-(1S,3R,20S,24aR)-24a-(4-methylthien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol(5Z,7E)-(1S,3R,20S124aS)-24a-(4-methylthien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol(5Z,7E)-(1S,3R,20S)-1,3-dihydroxy-24a-(4-methylthien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one(5Z,7E)-(1S,3R,24R)-24-(4-methylthien-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol(5Z,7E)-(1S,3R,24S)-24-(4-methylthien-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol(5Z,7E)-(1S,3R)-1,3-dihydroxy-24-(4-methylthien-2-yl)-9,10-secochola-5,7,10(19)-trien-24-one(7E)-(1R,3R,20S,24aR)-24a-(thien-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R,20S,24aS)-24a-(thien-2-yl)-24-a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R,20S)-1,3-dihydroxy-24a-(thien-2-yl)-24-a-homo-19-nor-9,10-secochola-5,7-dien-24a-one(5Z,7E)-(1S,3R,20S,24aR)-24a-(thien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol(5Z,7E)-(1S,3R,20S,24aS)-24a-(thien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol(5Z,7E)-(1S,3R,20S)-1,3-dihydroxy-24a-(thien-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-trien-24a-one(5Z,7E)-(1S,3R,24R)-24-(thien-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol(5Z,7E)-(1S,3R,24S)-24-(thien-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24a-triol(5Z,7E)-(1S,3R)-1,3-dihydroxy-24-(thien-2-yl)-9,10-secochola-5,7,10(19)-trien-24-one(5Z,7E)-(1S,3R,24S)-24-(4-methylthiazol-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol(5Z,7E)-(1S,3R,24R)-24-(4-methylthiazol-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol(5Z,7E)-(1S,3R)-1,3-dihydroxy-24-(4-methylthiazol-2-yl)-9,10-secochola-5,7,10(19)-trien-24-one(5Z,7E)-(1S,3R,24S)-24-(thien-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol(5Z,7E)-(1S,3R,24R)-24-(thien-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol(5Z,7E)-(1S,3R)-1,3-dihydroxy-24-(thien-2-yl)-9,10-secochola-5,7,10(19)-trien-24-one(5Z,7E)-(1S,3R,24S)-24-(4-methylthien-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol(5Z,7E)-(1S,3R,24R)-24-(4-methylthien-2-yl)-9,10-secochola-5,7,10(19)-triene-1,3,24-triol(5Z,7E)-(1S,3R)-1,3-dihydroxy-24-(4-methylthien-2-yl)-9,10-secochola-5,7,10(19)-trien-24-one(7E)-(1R,3R,24aR)-24a-fluoro-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3-diol(7E)-(1R,3R,24aS)-24a-fluoro-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3-diol(5Z,7E)-(1S,3R,24aR)-24a-fluoro-24a-(thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3-diol(5Z,7E)-(1S,3R,24aS)-24a-fluoro-24a-(thiazol-2-yl)-24a-homo-9,10-secochola-5,7,10(19)-triene-1,3-diol(7E)-(1R,3R,24aR)-24a-(acetyloxy)-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R,24aS)-24a-(acetyloxy)-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R,24aR)-24a-(2,2-dimethylpropanoyloxy)-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R,24aS)-24a-(2,2-dimethylpropanoyloxy)-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol(7E)-(1R,3R)-2-bromo-24a-(thiazol-2-yl)-24a-homo-19-nor-9,10-secochola-5,7-diene-1,3,24a-triol.6. Process for the production of compounds of general formula Iaccording to claim 1, in which Q means C₂-C₅ alkyl, characterized inthat a compound of formula III

by introduction of a protective group Y₄ into a compound of formula IV

in which Y₄ means a trialkylsilyl protective group, a mixedaryl-alkyl-substituted silyl protective group, a tetrahydropyranyl groupor a tetrahydrofuranyl protective group, is converted by oxidativecleavage of the double bond into a compound of general formula V

the alcohol is converted by introduction of any leaving group L into acompound of general formula VI

in which L means any leaving group, and Y₄ represents a trialkylsilylprotective group, a mixed aryl-alkyl-substituted silyl protective group,a tetrahydropyranyl protective group or a tetrahydrofuranyl protectivegroup, with an alkinol of formula

in which Y₅ represents a tetrahydropyranyl group or a benzyl group, andn means the number 0, 1, 2, 3, which is deprotonated with a suitablebase such as sodium hydride, potassium hydride, butyllithium, sodiumhydride, is reacted to a compound of general formula VIIb

in which Y₃ has the indicated meaning, in any sequence the triple bondis hydrogenated and optionally the still present protective group Y₅ iscleaved in the usual way to obtain the compound of general formula VIIIb

whose free hydroxy group then is converted with suitable oxidizingagents, such as pyridinium chlorochromate, pyridinium dichromate, Swernoxidation, Collins oxidation, into the aldehyde of general formula IXb,

which is converted by reaction with a nucleophile Z′, which representsany nucleophilic form of the above-defined radical Z, conversion of thefree hydroxy group in a group OCOR′ with R′ in the meaning of C₁-C₅alkyl, cleavage of protective group Y₄ and oxidation of the free hydroxygroup into the ketone of general formula XIIIb,

which then is converted in the usual way by Wittig reaction with one ofthe known phosphonates of formulas XIV, XV or XVI

after cleavage of the protective groups into a compound of generalformula I.
 7. Intermediate products of general formulas VIIb

according to-the process of claim 5, whereby radicals Y₄, Y₅ and n havethe meanings that are indicated there.
 8. Pharmaceutical preparationsthat contain at least one compound according to claim 1 together withpharmaceutically compatible adjuvants and vehicles.
 9. Use of thevitamin D derivatives of general formula I according to claim 1 for theproduction of pharmaceutical agents.
 10. Use according to claim 9 fortreating diseases that are characterized by hyperproliferation anddeficient cell differentiation (e.g., hyperproliferative diseases of theskin: psoriasis, pityriasis subia pilasis, acne, ichthyosis; pruritus;tumor diseases and precancerous stages: tumors of the intestines,carcinomas of the breast, lung tumors, prostate carcinomas, leukemias,T-cell lymphomas, melanomas, Betazell carcinoma, squamous carcinoma,actinic keratoses, cervix dysplasias, and metastasizing tumors of anytype).
 11. Use according to claim 9 for treatment and prophylaxis ofdiseases that are characterized by a disequilibrium of the immune system(e.g., eczemas and diseases of the atopic Formon series and inflammatorydiseases: rheumatoid arthritis, respiratory tract diseases such asasthma, auto-immune diseases, such as multiple sclerosis, diabetesmellitus type I, myasthenia gravis, lupus erythematosus, scleroderma,bullous skin diseases, such as pemphigus, pemphigoid, further rejectionreactions in the case of autologous, allogeneic or xenogeneictransplants, as well as AIDS).
 12. Use according to claim 10 incombination with other substances that have an immunosuppressive action,such as cyclosporin A, FK 506, rapamycin and anti-CD4-antibodies. 13.Use according to claim 9 for therapy of secondary hyperparathyroidismand renal osteodystrophia as well as diabetes mellitus type II.
 14. Useaccording to claim 9 for accelerated healing in topical administrationas well as for treatment of skin ageing or medicinally induced skinatrophy.
 15. Use according to claim 9 for treatment of diseases thataccompany disrupted hair growth or for supporting physiological hairgrowth.
 16. Use according to claim 9 for therapy and prophylaxis ofsenile osteoporosis, postmenopausal osteoporosis, steroid-inducedosteoporosis, and for accelerated healing of arthroplasties.
 17. Useaccording to claim 9 for treatment of degenerative diseases of theperipheral and central nervous system.
 18. Use of compounds of generalformula I, which antagonize the calcitriol action, according to claim 9for therapy and prophylaxis of arteriosclerosis, for therapy ofhypercalcemias, for birth control, in the case of AIDS, asimmunostimulants, in hirsutism and granulomatous diseases.
 19. Processfor the production of compounds of general formula IIa

in which E means any side chain, R₇, R₈, independently of one another,mean a hydrogen atom, a methyl group, or together an exocyclic methylenegroup or a cyclopropyl ring, Y₂ means a hydrogen atom or a group—(CO)R₅, Y₃ means a hydrogen atom or a hydroxy group, a halogen atom, agroup —O(CO)R₅ or an OR₅ group, whereby R₅ stands for an aliphaticC₁-C₁₂ alkyl radical, which optionally is interrupted by 1-2 oxygenatoms, 1-2 sulfur atoms and/or 1-2 NH groups and/or optionally issubstituted by 1-2 hydroxy groups, 1-2 amino groups, 1-2 SH groups, 1-2COOH groups and/or 1-2 phenyl groups, or for an aromatic radical with 5to 12 C atoms, Y₅ means a fluorine atom, a (CH₂)_(n)—OH group or a(CH₂)_(n)—O(CO) group, whereby n=0 to 4, and optionally present hydroxygroups are optionally present in protected form, which is characterizedin that a ketone of general formula XIIIc

in which E means any side chain and optionally existing keto groupsand/or hydroxy groups are present in protected form is converted byreaction with trimethylsilylacetic ester in the presence of a base,such-as, e.g., n-butyllithium or lithium aluminum hydride or with asuitable Wittig reagent in an aprotic solvent such as toluene,tetrahydrofuran, diethyl ether or dioxane into a compound of generalformula XXXIVc

in which Y₆ means a C₁-C₆ alkyl group, a benzyl group, or a phenylgroup, the ester group is converted by reaction with a reducing agentsuch as Dibah, lithium aluminum hydride, diborane or RedAl in hexane,toluene, tetrahydrofuran, diethyl ether or dioxane into the allylalcohol of general formula XXXVc

the allyl alcohol is converted in a way that is known in the art into acompound of general formula XXXVc

in which L means any leaving group (halogen, mesylate, tosylate,triflate, nonaflate), which is isolated or optionally produced in situand immediately further reacted to a Wittig reagent of general formulaXXXVIc,

in which G means a C₁-C₁₀ alkyl group, a C₁-C₁₀ alkoxy group, a phenylradical or a phenoxy radical, which then is reacted under knownconditions with a ketone of general formula XXXIIIc

in which Y′₃ means a hydrogen atom, a halogen atom or a protectedhydroxy group, a group —O(CO)R₅ or an OR₅ group, and Y₅ R₇ and R₈ havethe above-indicated meaning, and if desired, protective groups arecleaved.
 20. Intermediate products of the process according to claim 8of general formula XXXIVc,

in which E and G have the above-indicated meanings.